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Witalisz-Siepracka, A. JAK inhibitors and immune system. Encyclopedia. Available online: https://encyclopedia.pub/entry/10570 (accessed on 16 November 2024).
Witalisz-Siepracka A. JAK inhibitors and immune system. Encyclopedia. Available at: https://encyclopedia.pub/entry/10570. Accessed November 16, 2024.
Witalisz-Siepracka, Agnieszka. "JAK inhibitors and immune system" Encyclopedia, https://encyclopedia.pub/entry/10570 (accessed November 16, 2024).
Witalisz-Siepracka, A. (2021, June 07). JAK inhibitors and immune system. In Encyclopedia. https://encyclopedia.pub/entry/10570
Witalisz-Siepracka, Agnieszka. "JAK inhibitors and immune system." Encyclopedia. Web. 07 June, 2021.
JAK inhibitors and immune system
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13112611

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is aberrantly activated in many malignancies. Inhibition of this pathway via JAK inhibitors (JAKinibs) is therefore an attractive therapeutic strategy underlined by Ruxolitinib (JAK1/2 inhibitor) being approved for the treatment of myeloproliferative neoplasms. As a consequence of the crucial role of the JAK-STAT pathway in the regulation of immune responses, inhibition of JAKs suppresses the immune system. This review article provides a thorough overview of the current knowledge on JAKinibs’ effects on immune cells in the context of hematological malignancies. We also discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of the malignancy.

JAK STAT JAK inhibitor leukemia NK cells T cells

1. JAK-STAT Signaling in Hematological Malignancies

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals downstream of growth factor, hormone, and cytokine receptors. Thereby the JAK-STAT pathway regulates development, survival, proliferation, differentiation, and functionality of cells within the immune system [1][2][3][4][5].

The four JAKs, JAK1-3, and TYK2, are non-receptor tyrosine kinases which associate with their respective receptors. While some receptors associate with a pair of a specific JAK-family member, others are linked to more than one JAK. Ligand binding induces oligomerization of transmembrane receptors and activation of JAKs by auto- and/or trans-phosphorylation events. Subsequently, JAKs phosphorylate tyrosine residues on the receptors representing docking sites for STATs (STAT1-6) via their Src homology 2 (SH2) domain. Upon phosphorylation, STATs undergo a conformation change and switch from an anti-parallel to a parallel homo/heterodimer and translocate to the nucleus to regulate gene expression [2][3][5][6][7][8][9]. Additional posttranslational modification, formation of multimeric complexes with co-factors, and epigenetic remodeling processes add to the complexity of the transcriptional regulation initiated by the JAK-STAT signaling pathway and allow for its diverse functional consequences [5][6][10]. JAK1 is key for interferon (IFN) signaling, in combination with JAK2 in case of IFN-γ and with TYK2 in case of type I and type III IFN signaling. Together with JAK3, which is directly associated with the common γ chain (γc) of cytokine receptors, JAK1 signals downstream of the γc-dependent cytokines interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK2 is responsible for signaling downstream of erythropoietin (EPO), thrombopoietin (TPO), growth hormone, prolactin, leptin, IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). JAK1, JAK2, and, in some cases, TYK2 are activated by gp130 cytokine family members (IL-6, IL-11, IL-31, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), leukemia inhibitor factor (LIF), cardiotropin-1 (CT-1), neurotrophin-1 (NNT-1)) and IL-13. TYK2 is involved in signaling of IL-10-like cytokines (IL-10, IL-19, IL-20, IL- 22, IL-24, and IL-26) in conjunction with JAK1 and mediates IL-12/IL-23 cytokine signaling together with JAK2 [8][11][12].

Deregulated JAK-STAT signaling in the hematopoietic system is associated with a wide range of alterations, including immunodeficiency, autoimmunity, and transformation [4][5][13][14]. The discovery of hyperactivation of JAK-STAT pathway members in inflammatory pathologies (such as rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease) and hematological cancers triggered the development of JAK inhibitors (JAKinibs) as potential treatment options [4][15][16]. In cancer, aberrant activation of the JAK-STAT pathway is achieved by different means, including deregulated upstream signals or feedback loops, gene amplifications, generation of fusion proteins as well as gain-of-function (GOF) mutations [4][17]. The latter will be discussed in more detail below focusing on hematological malignancies. Dysregulated JAK-STAT signaling also plays a role in solid cancers, as reviewed before [4][18][19].

An overview of GOF mutations in the JAK-STAT signaling pathway occuring in hematological malignancies is presented in Table 1. JAKs consist of multiple domains, including an N-terminal FERM domain and an SH2-like domain that promote receptor interaction, a pseudokinase domain (JH2) with regulatory capacity, and the C-terminal catalytically active kinase domain (JH1) [4][20][21][22][23][24]. GOF mutations in JAKs are frequently located in the JH2 domain, where they lead to an altered auto-inhibitory function and render JAKs constitutively active [22][25]. The most prominent example is the somatic JAK2V617F mutation that is highly prevalent in myeloproliferative neoplasms (MPNs). MPNs, including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), are a group of diseases in which myeloid precursors produce increased numbers of blood cells with the potential to evolve into acute myeloid leukemia (AML) [26][27][28][29][30][31][32][33][34][35]. The equivalent germline JAK2V617I mutation, besides other pseudokinase domain mutations, has been described in hereditary essential thrombocytosis [36][37][38]. The corresponding somatic JAK1 JH2 mutations (V658I or V658F) are present in patients with acute lymphoblastic leukemia (ALL), T-cell prolymphocytic leukemia (T-PLL), and myeloid malignancies [4][15][25][39][40][41][42]. Somatic JH2 mutations are also found in JAK3 (e.g., A572V and A573V) in T-cell malignancies (T-PLL, T-ALL, early T-cell precursor ALL (ETP-ALL)), AML, and malignancies of natural killer (NK) cell origin (e.g., extranodal NK/T-cell lymphoma (NKTCL)) [4][41][43][44][45][46][47][48][49][50][51][52][53]. Rare cases of somatic and germline JH2 mutations in TYK2 have been described that are associated with ALL [4][54][55][56]. Other activating JAK mutations associated with hematological malignancies are found in the FERM, linker, and JH1 domain [4][15][32][57].

Table 1. Overview on JAK-STAT gain-of-function (GOF) mutations in hematological malignancies.

JAK/
STAT		 Type of mutations Hematological
malignancies 1		 Examples for
JAKinib sensitivity		 References
JAK1 somatic GOF(e.g., JAK1S646F, JAK1S646P, JAK1V658I) ALL (B-ALL, ETP-ALL, adult T-ALL), T-PLL, BIA-ALCL, ALK- ALCL, AML, MPN-unclassifiable, CMML Ba/F3 cells expressing JAK1S646F, JAK1S646P, or JAK1V658I are sensitive to JAKinibs, including Ruxolitinib. [4][15][39][40][41][42][51][58][59][60][61][62]
JAK2 germline GOF(e.g., JAK2R564Q, JAK2V617I) hereditary essential thrombocytosis Ba/F3-MPL cells expressing JAK2R564Q are more sensitive to Ruxolitinib than JAK2V617F-expressers. [36][37][38]
somatic GOF(e.g., JAK2V617F) MPN (PV > ET, PMF), AML, pediatric, and DS-ALL Ruxolitinib is approved for treatment of MPN. [26][27][28][29][30][31][32][33][34][35]
JAK3 germline GOF(JAK3Q507P) familial CLPD-NK   [63]
somatic GOF(e.g., JAK3M511I, JAK3A572V, JAK3A573V) ALL (ETP-ALL, T-ALL), ATLL, T-PLL, AML, (DS-)AMKL, NKTCL Ba/F3 cells expressing JAK3M511I or JAK3A573V are sensitive to Tofacitinib. JAK3A573V mutant NKTCL, and JAK3M511I mutant T-ALL-like disease models are responsive to Tofacitinib treatment in vivo. [4][15][41][43][44][45][46][47][48][49][50][51][52][53][64][65][66]
TYK2 germline GOF(TYK2G716V, TYK2P760L) pediatric ALL (B-ALL, T-ALL)   [55][56]
somatic GOF(e.g., TYK2E957D) T-ALL Ba/F3 cells expressing TYK2E957D are sensitive to JAK inhibitor I. [54][56]
STAT3 germline GOF(e.g., STAT3K392R) pediatric LGLL   [67]
somatic GOF(e.g., STAT3Y640F, STAT3D661Y/I/V/H) T-LGLL, NK-LGLL, ALK-ALCL, HSTL, DLBCL NOS, NKTCL, CLPD-NK, ANKL, Sezary syndrome Tofacitinib could be a promising salvage therapy for refractory T-LGLL patients with or without STAT3 mutations. [68][69][70][71][72][73][74][75][76][77]
STAT5B somatic GOF(e.g., STAT5BN642H, STAT5BY665H/F) NKTCL, ANKL, NK-LGLL, T-LGLL, T-PLL, T-ALL, MEITL, HSTL, PCTL, Sezary Syndrome, PTCL-NOS, AML, AAA, CNL, Eosinophilia STAT5BN642H-driven CD8+ T-cell disease and CD56+ T-LGL (NKT) leukemia models are sensitive to Ruxolitinib. STAT5BN642H T-ALL is sensitive to JAK1/JAK3 inhibitors. [78][68][69][79][80][81][75][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102]
STAT6 somatic GOF(e.g., STAT6D419H/G/A) CHL, FL, RR-DLBCL, PMBCL STAT6D419-missense mutated PMBCL cell lines are sensitive to JAK2 inhibitors. [103][104][105][106]

1 Abbreviations: AAA—acquired aplastic anemia; ALK-ALCL—anaplastic lymphoma kinase negative anaplastic large cell lymphoma; ALL—acute lymphoblastic leukemia; AML—acute myeloid leukemia; ANKL—aggressive natural killer cell leukemia; ATLL—adult T-cell leukemia lymphoma; B-ALL—B-cell acute lymphoblastic leukemia; BIA-ALCL—breast implant-associated anaplastic large cell lymphoma; CHL—classical hodgkin lymphoma; CLPD-NK—chronic lymphoproliferative disorders of natural killer cells; CMML—chronic myelomonocytic leukemia; CNL—chronic neutrophilic leukemia; DLBCL NOS—diffuse large B-cell lymphoma, not-otherwise-specified; DS-ALL—down syndrome acute lymphoblastic leukemia; (DS)-AMKL—(down syndrome) acute megakaryoblastic leukemia; ET—essential thrombocythemia; ETP-ALL—early T-cell precursor ALL; FL—follicular lymphoma; HSTL—hepatosplenic T-cell lymphoma; LGLL—large granular lymphocytic leukemia; MEITL—monomorphic epitheliotropic intestinal T cell lymphoma; MPN—myeloproliferative neoplasm; NK-LGLL—natural killer cell large granular lymphocytic leukemia; NKTCL—extranodal NK/T-cell lymphoma; PMBCL—primary mediastinal B-cell lymphoma; PMF—primary myelofibrosis; PCTL—primary cutaneous γδ T-cell lymphoma; PTCL-NOS—peripheral T-cell lymphoma not-other-specified; PV—polycythemia vera; RR-DLBCL—relapsed-refractory diffuse large B-cell lymphoma; T-ALL—T-cell acute lymphoblastic leukemia; T-LGLL—T-cell large granular lymphocytic leukemia; T-PLL—T-cell prolymphocytic leukemia.

GOF mutations in STATs have also been described in hematological malignancies [5][10][107] and most frequently occur in the SH2 domain, which is required for dimerization and transcriptional activity. SH2 domain mutations of STAT3 (e.g., Y640F, D661Y) and STAT5B (e.g. N642H, Y665F/H) are found in mature T-cell and NK-cell neoplasms (see Table 1 for details of cancer subtypes), T-ALL, diffuse large B-cell lymphoma (DLBCL) and myeloid diseases (eosinophila, AML, chronic neutrophilic leukemia) [78][68][69][79]. Activating STAT mutations do also exist outside of the SH2 domain in hematological cancers [68][70][67][71] and DNA binding domain mutations of STAT6 are associated with B-cell malignancies [103][104][105][106].

The identification of JAK2V617F as a driver mutation in the majority of PV cases and in over 50% of ET and PMF cases was a major breakthrough and provided the rationale for the development of JAKinibs [26][27][28][108]. Ruxolitinib (JAK1/2 inhibitor) has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of intermediate and high risk PMF and secondary MF and second line for PV patients resistant or intolerant to hydroxyurea [109]. JAKinib treatment prolongs overall survival and reduces splenomegaly typically associated with MPNs, but does not induce complete remission. Importantly, Ruxolitinib triggers comparable therapeutic responses in MPN patients irrespective of the JAK2V617F mutation. Patients harboring deletions in the calreticulin gene (CALR) or mutations in the MPL receptor also show therapeutic responses as the constitutive activation of the JAK-STAT pathway represents a common feature of MPNs. As a consequence, JAKinibs are extensively tested in (pre)clinics as therapies for a variety of malignancies with overactivation of the JAK-STAT pathway due to mutations (see Table 1) or due to constitutive activation of the pathway. As such, diseases driven by the STAT5BN642H mutation are partially responsive to Ruxolitinib [80][81]. Table 2 summarizes ongoing clinical trials for JAKinib treatment of hematological malignancies.

Table 2. Ongoing clinical trials for JAKinibs in hematological malignancies (as for April 2021).

NCT number JAKinib Phase Disease(s) 2
NCT02723994 Ruxolitinib (JAK1/2) 2 ALL
NCT03571321 1 ALL (Ph-like)
NCT03874052 1 AML
NCT03286530 2 AML
NCT04055844 2 AML, MDS
NCT03654768 2 CML
NCT03610971 2 CML (chronic phase)
NCT03722407 2 CMML
NCT03801434 2 Eosinphilic syndromes
NCT04669210 2 GvHD, HSCT complications, ALL, AML
NCT02613598 1 (Non)Hodgkin Lymphoma
NCT03681561 1/2 Hodgkin Lymphoma
NCT03017820 1 Leukemia/lymphoma
NCT03878199 1/2 MPN
NCT04281498 2 MPN
NCT04041050 1 MPN
NCT02158858 1/2 MPN, MDS
NCT03558607 1/2 sAML
NCT01712659 1/2 T-cell Leukemia
NCT03613428 1/2 T-cell Leukemia
NCT03117751 2/3 T-cell Leukemia/Lymphoma
NCT02974647 2 T/NK lymphoma
NCT04282187 Ruxolitinib (JAK1/2) or Fedratinib (JAK2) 2 MPN, AML
NCT04282187 Fedratinib (JAK2)   MPN, AML
NCT03598959 Tofacitinib (JAK1/3) 2 T/NK lymphoma
NCT04640025 Itacitinib (JAK1) 2 MF
NCT01633372/NCT04629508 2 MPN
NCT03144687 2 MPN
NCT04061421 1/2 MDS/MPN
NCT03697408 1/2 classical HL
NCT02760485 1/2 Relapsed or Refractory DLBCL
NCT01905813 1 B-cell Malignancies (previously treated)
NCT02018861/NCT04509700 1/2 B-cell Malignancies (previously treated)
NCT03989466 1 (recurrent) T-PLL
NCT04173494 Momelotinib (JAK1/2) 3 MPN (pMF, PV)
NCT03645824 Patricinib (JAK2) 2 MF
NCT03165734 3 MF (primary and secondary)
NCT02891603 1/2 GvHD

2 Abbreviations: ALL—Acute lymphoblastic leukemia; (s)AML—(secondary) acute myeloid leukemia; CML—Chronic myeloid leukemia; CMML—Chronic myelomonocytic leukemia; DLBCL—Diffuse Large B-Cell Lymphoma; GvHD—graft versus host disease; HL—Hodgkin lymphoma; HSCT—hematopoietic stem cell transplant; MDS—Myelodysplastic syndrome; MPN—myeloproliferative neoplasm; Ph—Philadelphia chromosome; (p)MF—(primary) myelofibrosis; T-PLL—T-cell-prolymphocytic leukemia. Search strategy: clinicaltrials.gov were searched for trials fulfilling following criteria: condition or disease—Leukemia/Lymphoma; other terms—name of JAKinib; excluded: terminated, withdrawn, suspended, or status unknown.

Activation of the JAK-STAT pathway by mutations mostly increases sensitivity to JAKinibs (as exemplified in Table 1), but no JAKinib is available that specifically targets a mutated allele. Such inhibitors may circumvent potential side-effects of current JAKinibs that also hit non-transformed cells [4].

2. JAK-STAT Signaling in the Immune System

The JAK-STAT pathway has a critical role in the development and function of immune cells. Loss-of-function (LOF) mutations in JAKs or STATs are associated with immune deficiencies or enhanced susceptibility to infections [5]. The most severe phenotype occurs in patients with LOF in signaling components downstream of γc-dependent cytokines, namely JAK3 and STAT5B, which manifest as severe combined immune deficiencies (SCIDs) [4][110]. The severe immune deficiency is predominantly linked to impaired IL-7 and IL-15 signaling [14]. Interestingly, STAT5B LOF mutations may also provoke autoimmune phenotypes due to non-functional T regulatory cells (Tregs) [111]. LOF mutations in STAT1 and TYK2 enhance the susceptibility to bacterial and viral infections [110][112], while LOF in STAT2 and STAT4 increase the incidence of viral and fungal infections, respectively [113][114][115][116]. Similarly, GOF mutations of STAT1 and STAT3 may suppress the immune system and manifest with impaired anti-viral, anti-bacterial, and for STAT1, also anti-fungal responses [110][117]. Knockout mice for JAKs and STATs generally recapitulate the phenotypes of patients with LOF mutations and provide a valuable tool to understand the molecular mechanisms of JAK-STAT signaling in diseases. The consequences of JAK and STAT knockouts in mice and LOF mutations in humans have been reviewed extensively and the most prominent immune phenotypes are summarized in Table 3. The availability of conditional knockouts provides the opportunity to overcome embryonic and perinatal lethality of JAK1, JAK2, STAT3, or STAT5A/B-deficient mice. Conditional knockouts for STAT3 and STAT5A/B allowed to uncover the effects of STAT3 and STAT5 in T-cell differentiation and memory, dendritic cell function, and NK-cell tumor surveillance (reviewed in [5]). Conditional JAK knockouts have not yet been studied in depth despite the severe immune defects of knockout mice. Inducible deletion of JAK1 markedly impairs stem cell homeostasis and reduces the frequencies of B cells [118]. Similarly, NK cell-specific deletion of JAK1 almost completely abrogates the presence of peripheral NK cells [119]. In contrast, inducible deletion of JAK2 fails to impact on lymphopoiesis [120] and NK cell-specific JAK2 deficiency does not interfere with NK-cell homeostasis [119]. JAK2-deficient T cells are skewed towards Th2 and Treg polarization resulting in reduced graft versus host disease (GvHD) [121]. In addition, NK cell-specific deletion of TYK2 decreases anti-bacterial responses while leaving NK cell-mediated tumor surveillance intact in contrast to global TYK2 knockout mice [122][123][124]. These studies highlight the importance of the JAK-STAT pathway for immune responses and point towards a potential risk for patients when drug-targeting the JAK-STAT pathway.

Table 3. Mutations in the JAK-STAT pathway resulting in patient’s immune dysfunctions and immunological phenotypes of respective knock-out/-in mice.

JAK/
STAT		 Type of mutations Immune phenotype of patients 3 Immune phenotype of knockout/-in mice References
JAK1 LOF (e.g., JAK1P733L; JAK1P832S) Immunodeficiency (early onset cancer and recurrent mycobacterial infections) Perinatally lethal; severe reduction of pre–B cells, and mature T and B lymphocytes [125][126]
JAK3 LOF (e.g., JAK3Y100C; JAK3D169E) autosomal recessive T-B+NK- SCID (null mutations), broader range of clinical immunosuppressive phenotypes Defective T, B, ILC (incl. NK) cell development [64][127][128][129][130][131][132][133]
TYK2 LOF (e.g., TYK2I684S) Mycobacterial and viral infections Impaired T and NK-mediated anti-viral, anti-bacterial, and anti-tumor responses [123][124][134][135][136][137][138]
STAT1 LOF (e.g., STAT1K201L; STAT1K211R) Complete deficiency: mycobacteria, virus infection; dysfunctional NK cells; partial deficiency: mycobacteria but no virus infection Impaired responses to Type I and Type II IFN, increased susceptibility to infections, impaired NK cells [139][140][141][142][143][144][145]
GOF (e.g., STAT1Y170N; STAT1C174R) viral, bacterial infections, combined immunodeficiency (reduced memory B, Th17 cells, impaired NK cells); autoinflammation, organ-specific autoimmune disorders Impaired IL-17 immunity [146][147][148][149][150]
STAT2 LOF (e.g., STAT2c.1836C4A) primary immunodeficiency (viral infections) Impaired response to Type I IFN and susceptibility to viral infections [113][114][151][152]
STAT3 LOF (e.g., STAT3Y657N) AD-HIES, primary immunodeficiency (susceptibilities to infections, impaired Th17 and B cells) Embryonically lethal [110][153][154][155]
GOF (e.g., STAT3Q344H) Immune deficiency (reduced memory B cells, NK cells, pDCs); various organ autoimmunity - [67][110][156]
STAT4 LOF (e.g., STAT4E651V) Fungal infections Inhibited Th1 differentiation [115][116][157]
STAT5B LOF (e.g., STAT5BA630P) combined immunodeficiency (Treg deficiency, reduced T cells and NK cells) serve viral infections; autoimmune symptoms Impaired NK and T cells [158][159][160][161][162][163][164]

3 Abbreviations: AD-HIES—autosomal dominant hyper-IgE syndrome; IFN—interferon; ILC—innate lymphocyte; NK—natural killer; pDC—plasmacytoid dendritic cells; SCID—severe combined immunodeficiency; Treg—T regulatory cells.

3. The Effects of JAKinibs on the Immune System: Focus on Cytotoxic Lymphocytes

JAKinibs provide a powerful tool in targeted cancer therapy. In light of the above-described immune alterations, JAKinibs are expected to provoke immune suppression. We here provide an overview of currently available JAKinibs undergoing clinical trials for treatment of hematological diseases and focus on their immune effects.

3.1. Ruxolitinib

Ruxolitinib (Jakavi®) successfully reduces the systemic symptoms of MPN patients [109] while it does not eliminate the malignant clone [165]. MPNs are characterized by the increased levels of pro-inflammatory cytokines that are associated with enhanced NF-κB signaling [166]. The enhanced cytokine production contributes to systemic symptoms and is of prognostic value in MF [167]. Malignant and non-malignant cells are the source of proinflammatory cytokines and the success of Ruxolitinib treatment depends on the suppression of chronic inflammation [168]. Thus, MPN requires Ruxolitinib treatment for a prolonged period, which also exerts immune suppressive effects [109]. A recent approval of Ruxolitinib for treatment of steroid-refractory acute GvHD underlines its potent repressive activity on the immune system [169]. In line, the 5-year follow-up study of the COMFORT-II clinical trial uncovered that Ruxolitinib-treated MPN patients manifest with neutropenia and leukopenia, urinary tract infections, pneumonia, sepsis, tuberculosis, and herpes zoster infections [170]. In the majority of case reports, severe viral or bacterial infections forced the discontinuation of the therapy (reviewed in [171]). A recent retrospective study failed to identify a significantly increased risk of infections in Ruxolitinib-treated MPN patients which may reflect the low number and heterogeneity of patients in the control group [172]. Porpaczy et al., reported a strongly increased risk for Ruxolitinib-treated patients to develop B-cell lymphoma [173]; this result is in contrast to other studies that reported an increased risk of skin cancer upon Ruxolitinib treatment [174][175][176]. Of note, lymphoma is a serious rare adverse event in RA patients treated with another JAK1/2 inhibitor Baricitinib [177]. It still remains to be determined whether there is an increased rate of infections or secondary malignancies in large patient cohorts, which is challenging for rare diseases such as MPNs.

The basic analysis of immune functions in several cell types clearly illustrates the immune suppressive effects of Ruxolitinib. NK cells are the first-line of defense against virally infected and transformed cells and crucially depend on IL-15/JAK1/3/STAT5 signaling for survival and function. Ruxolitinib-treated patients harbor decreased NK-cell numbers with an immature phenotype. In addition, in vitro Ruxolitinib treatment of healthy donor-derived NK cells impairs their cytotoxic activity [178]. Furthermore, Ruxolitinib interferes with the dendritic cell (DC)—NK cell interaction which is required for full blown activation [179]. This effect is linked to an impaired NK cell-intrinsic IL-15 signaling upon DC trans-presentation [180]. In addition, Ruxolitinib inhibits DC development and activation in vitro and in vivo and is also associated with an impaired DC migration and clearance of adenoviral infections in mice [181]. The reduced migration ability of DCs is caused by the off-target inhibition of Rho-associated coiled-coil kinases [182].

The suppressive effects of Ruxolitinib extend to adaptive immune cells. Three independent studies showed significantly reduced Treg numbers in Ruxolitinib-treated patients, an effect that occurs rapidly and is long-lasting [183][184][185]. Effects on other T-cell subtypes are less clear; reduced Th1 and Th17 cell numbers were observed in patients upon three weeks of treatment whereas another patient cohort failed to show any difference in total CD4+ or Th1 cell numbers after a three- or six-months treatment period [183][184]. In contrast, in a murine model of GvHD, Th1 cells were reduced and Treg numbers were increased in the Ruxolitinib-treated group [186]. In any case, T-cell activity is significantly impaired by Ruxolitinib via interference with the IL-2/JAK1/3/STAT5 pathway [183]. Opposing effects were observed for B cells, where Ruxolitinib treatment normalized the decreased numbers of B cells in MPN patients to physiological levels. The underlying mechanism remains enigmatic [187].

3.2. Tofacitinib

Tofacitinib (CP-690,550) is a JAK1/3 inhibitor with a lower affinity for JAK2 and is clinically used for the treatment of RA, psoriatic arthritis, and ulcerative colitis due to its immunosuppressive effects [16][188][189][190]. The immunosuppressive activity of Tofacitinib that is exploited in autoimmune diseases is linked to its ability to block signaling downstream of multiple cytokines. This results in a suppressed differentiation of pathogenic Th1 and Th17 cells and reduced pro-inflammatory signals by innate immune cells [191][192][193][194]. In animal models, Tofacitinib treatment reduces CD8+ T and NK-cell numbers and affects NK-cell differentiation [195][196][197][198], which is discussed to be the consequence of blocking γc-utilizing cytokines that are essential for lymphocyte survival and maturation [199][200][201]. Decreased lymphocyte numbers are associated with immunosuppression and prolong allograft survival and reduce delayed-type hypersensitivity (DTH), while impairing anti-tumor responses in an experimental lung metastasis mouse model of colon cancer [195][196][197][198][202]. In RA patients, long-term Tofacitinib treatment gradually decreased absolute lymphocyte (ALC) and T-cell counts. NK-cell numbers drop in a dose-dependent manner upon short-term Tofacitinib treatment, while they increase upon mid- to long-term treatment. The latter is discussed to be the consequence of increased IL-15 availability [194][203][204][205][206]. Of note, changes in lymphocyte numbers are reversible upon treatment withdrawal [194][205][206][207].

The reduced NK and T-cell numbers are associated with an only transient impairment of T-cell-mediated responses while NK-cell functions are consistently impaired even after treatment withdrawal in healthy volunteers [206]. Tofacitinib does not interfere with the viability of healthy donor NK cells but decreases IL-2-mediated NK-cell activation at concentrations used in RA patients. NK cells display an impaired NK-cell receptor expression, degranulation, cytotoxicity, and cytokine production [208]. In addition, Tofacitinib decreases expression levels of CD80/CD86 and thereby the T-cell stimulatory capacity of DCs through suppression of type I IFN signaling [209]. In contrast to effector T cells, Tregs appear less sensitive to Tofacitinib, as their numbers and suppressive activity are preserved upon treatment [206][210][211]. Similar to Ruxolitinib, B-cell numbers increase upon Tofacitinib treatment [194][205][207]. Despite a potential effect on B-cell maturation [212], humoral responses to vaccines are not affected by Tofacitinib, indicating a neglectable suppressive effect on B-cell functions [194][205][206][207].

The suppressive effects on T and NK cells translate into adverse effects of Tofacitinib including higher incidences of upper respiratory tract infections, pneumonia, and herpes zoster [194]. Initial reports did not show higher frequencies of lymphoma development in Tofacitinib-treated RA patients, but a slight increase in Epstein–Barr virus (EBV) association [208][213]. More recently, preliminary results from a safety clinical trial (NCT02092467) revealed an increased risk of malignancies, especially lung cancer, upon Tofacitinib treatment compared to treatment with tumor necrosis factor (TNF) inhibitors [214].

3.3. Fedratinib

Fedratinib (SAR-302503, TG-101348) has recently been approved for the treatment of intermediate-2 or high-risk primary or secondary MF. Fedratinib has a high specificity for JAK2 when compared to Ruxolitinib [215]. In addition, Fedratinib inhibits fms like tyrosine kinase 3 (FLT3) and bromodomain-containing protein 4 (BRD4). While the role of FLT3 inhibition in the therapeutic outcome is unclear, inhibition of BRD4 strongly diminishes NF-κB-driven pro-inflammatory cytokines which contribute to MPN pathology [166]. The anti-inflammatory effects of Fedratinib are comparable to the effects of Ruxolitinib but were assigned to BRD4 blockade rather than JAK1 inhibition [11]. The specificity of Fedratinib towards JAK2 predicts a less immune suppressive potential but clinical data on the risk of infections in large patient cohorts are still lacking. Clinical trials point at neutropenia and slightly higher frequencies of urinary tract infections upon Fedratinib treatment [215].

While it is well established that Fedratinib diminishes inflammation in MPN patients the exact effects on each (immune) cell type remains to be determined. NK-cell proliferation and function are less affected by Fedratinib than by Ruxolitinib. Although Fedratinib impairs IL-2 and soluble IL-15-mediated activation of STAT5 in NK cells, it does not interfere with the DC-dependent trans-presentation of IL-15 to NK cells [179]. It is attractive to speculate that this mechanism overrides any other effect in vivo rendering Fedratinib significantly less suppressive for NK cells. Of note, Fedratinib inhibits NK-cell development in vitro in a suppressor of cytokine signaling protein 2 (SOCS2)-deficient background by an unknown mechanism [216].

In vitro treatment of healthy donor peripheral blood mononuclear cells (PBMCs) with Fedratinib impairs DC maturation but retains the ability to induce T-cell proliferation which is in contrast to Ruxolitinib. JAK2 inhibition fails to block the IL-2/STAT5 pathway which accounts for the suppressive effect of Ruxolitinib on T cells [217]. Despite the fact that in vitro Treg numbers remain unaffected by Fedratinib [179], in vivo, a few patients react with decreased Treg numbers to Fedratinib treatment [184]. A more detailed analysis on the effects of Fedratinib for immune functions may be expected from the upcoming phase 4 trials.

3.4. Momelotinib

Momelotinib (CYT387) is a JAK1/2 inhibitor that is currently in phase 3 clinical trials for MF and shows equal therapeutic effects to Ruxolitinib in JAKinib-naive patients. The major advantage of Momelotinib is the fact that it induces anemia to a reduced extent [218][219]. The effects of Momelotinib on the immune system remain to be determined. The only information available so far is the comparable impairment of T-cell subsets upon in vitro treatment with Momelotinib and Ruxolitinib [220], which was expected as both drugs target the same spectrum of cytokines.

3.5. Pacritinib

Pacritinib (SB1518) is an inhibitor selective for JAK2, FLT3, interleukin receptor-associated kinase (IRAK), and Colony stimulating factor 1 receptor (CSF1R) and is currently undergoing phase 2/3 clinical trials for MPNs [221]. Pre-clinical data identified that AML cells are sensitive to Pacritinib due to its ability to inhibit IRAK signaling thereby providing a rationale for its use in AML irrespective of the JAK2 or FLT3 mutation status [222]. So far, only limited information regarding the risk for serious infections is available from clinical trials and only little data exist on its effects on immune cell subsets. In the context of GvHD, Pacritinib does not affect non-alloreactive T cells and Tregs which contrasts observations made with Ruxolitinib [121]. Confirmation of beneficial effects of Pacritinib in GvHD stems from a phase 1 clinical trial where combination of Pacritinib with mTOR inhibitors successfully limited acute GvHD [223]. Unexpectedly, Pacritinib has a pronounced effect on NK-cell activity in vitro [121], which is not observed for the JAK2/FLT3-specific inhibitor Fedratinib. The NK-cell effect of Pacritinib is thus most likely not related to JAK2. Preliminary data from our laboratory show that unlike Ruxolitinib, Pacritinib impairs cytotoxic activity of murine and human NK cells already upon short-term exposure. Long-term exposure abolishes this difference; NK-cell functions are impaired to the same extent irrespective of the inhibitor used. The effect of Pacritinib is not related to JAK2, as an impairment of cytotoxicity was also observed in JAK2-deficient NK cells. The nature of this off-target effect is currently unclear. Betts et al., speculated that Pacritinib affects NK cells by interfering with TYK2 [121]. This appears unlikely in view of the fact that TYK2 deficiency only in NK cells does not impair cytotoxicity [122].

3.6. Itacitinib

Itacitinib (INCB039110) is a potent JAK1-specific inhibitor with pronounced anti-inflammatory activity in preclinical disease models. It is currently undergoing clinical trials for treatment of autoimmune/inflammatory diseases and cancers [207][224]. Clinical trials in hematological malignancies are summarized in Table 2. In contrast to first generation pan-/multiple-JAK inhibitors, this JAK1-specific inhibitor holds the promise of dampening inflammation driven by JAK1-dependent cytokines (like IFN-γ, IL-6), while having reduced side effects [207][224][225][226]. Itacitinib efficiently inhibits IL-2-induced phosphorylation of STAT3 and STAT5 and thereby IL-2-mediated T-cell proliferation. It suppresses pro-inflammatory cytokine signaling, including IL-6 signaling, and IL-17 production by T cells upon IL-23 stimulation [224]. These anti-inflammatory and immunosuppressive effects were confirmed in vivo in rodent models of experimentally induced arthritis, inflammatory bowel disease and alloreactive inflammatory acute GvHD [224][227]. In an MHC-mismatched mouse model of acute GvHD, Itacitinib treatment reduced inflammatory cytokine levels (including IFN-γ, TNF-α, IL-6, IL-13, and IL-1β) and T-cell numbers in the inflamed colon tissue. In contrast, T-cell numbers in blood and spleen remained unaffected. Interestingly, graft-versus-leukemia responses in this mouse model were preserved upon Itacitinib treatment [227][228]. While Itacitinib treatment did not drastically affect Tregs numbers, it was associated with a decreased level of activated HLA-DR+CD38+ Tregs [228].

Preliminary data point towards good clinical efficacy of Itacitinib in autoimmune diseases [207][229][230][231][232], but no significant effect was observed in a trial for GvHD compared to corticosteroids (NCT03139604) [224]. Of note, the clinical potential of Itacitinib for prevention of cytokine release syndrome in patients treated with anti-CD19 CAR-T cells is currently being investigated (NCT04071366) [226]. Itacitinib is also explored for its anti-tumor activities in MPNs and B-cell malignancies as mono- or combination-therapy (Table 2). The potential and efficacy of JAK1-specific inhibitors in comparison to first-generation JAKinibs regarding their anti-tumor, anti-inflammatory, or immunosuppressive effects in different disease entities still awaits further evaluation.

4. When an Immune Cell Becomes Cancerous—Hijacking JAKinibs’ Immunosuppressive Side Effects for Treatment of NK/T-Cell Tumors

The strong suppressive effects of Ruxolitnib on NK and T cells are now exploited for the treatment of hematological diseases originating from cytotoxic lymphocytes including NKTCL, aggressive NK-cell leukemia (ANKL), and T-cell lymphomas/leukemias. NKTCL and ANKL are aggressive diseases with poor prognosis. They harbor alterations of the JAK-STAT signaling pathway, including STAT3 mutations and mutations in epigenetic modifiers [75][84][93]. Drug screens revealed a synergistic activity of the JAK1/2 inhibitor Ruxolitinib in combination with the BCL2 inhibitor Venetoclax in NKTCL and ANKL cell lines [93]. A synergistic efficacy of Ruxolitinib and BCL2 inhibitors was also shown in T-cell lymphoproliferative diseases, including T-ALL and human T-cell leukemia virus type 1 (HTLV1)-associated adult T-cell leukemia (ATL) [233][234][235][236]. A synergistic growth inhibitory effect in NKTCL cell lines was also achieved by a combination of Ruxolitinib with the CDK4/6 inhibitor Ribociclib (LEE011) [237]. This indicates that Ruxolitinib might not only be efficient in myeloid malignancies, but could also be of therapeutic value for patients with lymphoid malignancies [93][238][239][240][241][242]. Clinical trials using Ruxolitinib are ongoing for treatment of different cancer entities, such as HTLV1-associated ATL (NCT01712659), relapsed/refractory ETP-ALL (NCT03613428), relapsed/refractory NK-cell or peripheral T-cell non-Hodgkin Lymphoma (NCT01431209, NCT02974647), and ALL (NCT03117751). Similarly, the inhibitory effects of Itacitinib on T-cell proliferation [226] may be repurposed to block transformed T-cell growth. Indeed, there is a clinical trial ongoing for the use of Itacitinib in combination with Alemtuzumab (anti-CD52) in T-PLL patients (NCT03989466) [243]. A therapeutic window remains to be determined at which Itacitinib exerts anti-tumor effects, while avoiding counterproductive immunosuppressive effects.

As described above, Tofacitinib potently inhibits T and NK cells in a time and dose-dependent manner. Therefore, it might be an option to treat malignancies derived from innate and adaptive lymphocytes. As indicated in Table 1, BaF3 cells expressing JAK3 mutations as well as JAK3-mutant T-ALL and NKTCL in vivo models are sensitive to Tofacitinib treatment [44][53][66]. Similarly, NKTCL cell lines with constitutive activation of JAK-STAT signaling, partially associated with JAK3 GOF mutations, respond to Tofacitinib [45][50][53][93][244]. A phase 2 clinical trial currently includes patients with relapsed/refractory NKTCL that are treated with a combination of Tofacitinib and the histone deacetylase inhibitor Chidamide (Table 2). First case reports demonstrated a moderate activity of the combined use of Tofacitinib and Ruxolitinib in T-PLL [243][245][246]. Tofacitinib inhibits STAT5-regulated miR-21 expression in cutaneous T-cell lymphoma (CTCL) and thereby blocks anti-apoptotic effects of miR-21 in malignant T cells [238][247]. Combination of the BCL2 inhibitor Venetoclax with Tofacitinib induced therapeutic responses in some hematological patients with relapsed/refractory T-ALL with surface IL-7R expression or IL-7R-pathway mutations and BCL2 expression [248]. In contrast, Tofacitinib was not effective in a patient with DDX3X-MLLT10 T-ALL carrying an activating JAK3 mutation [249]. Therefore, the individual genetic make-up of a hematological malignancy might determine its responsiveness to Tofacitinib treatment.

Tofacitinib is a promising therapeutic strategy also for large granular lymphocytic leukemia (LGLL)—a rare subtype of mature T- and NK-cell neoplasms that is characterized by clonal expansion of cytotoxic NK or T lymphocytes. LGLL has a largely indolent course and is frequently associated with autoimmune disorders [250][251][252][253]. T-cell LGLL (T-LGLL) in particular is associated with rheumatoid arthritis in 10–30% of the patients [254][255][256]. Other autoimmune disorders associated with LGLL are autoimmune-related cytopenia including neutropenia [251][253][257]. Deregulation of pro-survival pathways, including a deregulated JAK-STAT signaling, have been implicated in disease pathogenesis and support the expansion of auto-reactive lymphocytes [78][250][251][252][253]. T-LGLL shows a high proportion of somatic STAT3 GOF mutations [72][73][74][99]. Based on its immunosuppressive activity, Tofacitinib was studied as a salvage therapy for highly refractory T-LGLL with RA, showing encouraging response rates with improvement of RA and cytopenia symptoms and limited side effects [76]. Tofacitinib selectively induces apoptosis in STAT3-mutant T-LGLL cells compared to healthy CD8+ T cells [76]. There is hope that the suppressive effects of Ruxolitinib, Tofacitinib, and potentially Itacitinib on cytotoxic lymphocytes will be repurposed as novel therapies in NK/T-cell malignancies with Tofacitinib holding promise for specific types of leukemias associated with autoimmune symptoms [258].

References

  1. Schindler, C.; Levy, D.E.; Decker, T. JAK-STAT Signaling: From Interferons to Cytokines. J. Biol. Chem. 2007, 282, 20059–20063.
  2. O’Shea, J.J.; Plenge, R. JAK and STAT Signaling Molecules in Immunoregulation and Immune-Mediated Disease. Immunity 2012, 36, 542–550.
  3. Stark, G.R.; Darnell, J.E., Jr. The JAK-STAT Pathway at Twenty. Immunity 2012, 36, 503–514.
  4. Hammarén, H.M.; Virtanen, A.T.; Raivola, J.; Silvennoinen, O. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine 2019, 118, 48–63.
  5. Villarino, A.V.; Kanno, Y.; O’Shea, A.V.V.Y.K.J.J. Mechanisms and consequences of Jak–STAT signaling in the immune system. Nat. Immunol. 2017, 18, 374–384.
  6. Levy, D.E.; Darnell, J.E., Jr. STATs: Transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 2002, 3, 651–662.
  7. Shuai, K.; Liu, B. Regulation of JAK–STAT signalling in the immune system. Nat. Rev. Immunol. 2003, 3, 900–911.
  8. Kiu, H.; Nicholson, S.E. Biology and significance of the JAK/STAT signalling pathways. Growth Factors 2012, 30, 88–106.
  9. Morris, R.; Kershaw, N.J.; Babon, J.J. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018, 27, 1984–2009.
  10. Villarino, A.; Kanno, Y.; Ferdinand, J.R.; O’Shea, J.J. Mechanisms of Jak/STAT Signaling in Immunity and Disease. J. Immunol. 2015, 194, 21–27.
  11. McLornan, D.P.; Khan, A.A.; Harrison, C.N. Immunological Consequences of JAK Inhibition: Friend or Foe? Curr. Hematol. Malign- Rep. 2015, 10, 370–379.
  12. Gadina, M.; Johnson, C.; Schwartz, D.; Bonelli, M.; Hasni, S.; Kanno, Y.; Changelian, P.; Laurence, A.; O’Shea, J.J. Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. J. Leukoc. Biol. 2018, 104, 499–514.
  13. Casanova, J.-L.; Holland, S.M.; Notarangelo, L.D. Inborn Errors of Human JAKs and STATs. Immunity 2012, 36, 515–528.
  14. O’Shea, J.J.; Holland, S.M.; Staudt, L.M. JAKs and STATs in Immunity, Immunodeficiency, and Cancer. New Engl. J. Med. 2013, 368, 161–170.
  15. Senkevitch, E.; Durum, S. The promise of Janus kinase inhibitors in the treatment of hematological malignancies. Cytokine 2017, 98, 33–41.
  16. Schwartz, D.M.; Kanno, Y.; Villarino, A.; Ward, M.; Gadina, M.; O’Shea, J.J. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 2017, 16, 843–862.
  17. Chen, E.; Staudt, L.M.; Green, A.R. Janus Kinase Deregulation in Leukemia and Lymphoma. Immunity 2012, 36, 529–541.
  18. Thomas, S.J.; Snowden, J.A.; Zeidler, M.; Danson, S. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br. J. Cancer 2015, 113, 365–371.
  19. Igelmann, S.; Neubauer, H.A.; Ferbeyre, G. STAT3 and STAT5 Activation in Solid Cancers. Cancers 2019, 11, 1428.
  20. Saharinen, P.; Takaluoma, K.; Silvennoinen, O. Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain. Mol. Cell. Biol. 2000, 20, 3387–3395.
  21. Saharinen, P.; Vihinen, M.; Silvennoinen, O. Autoinhibition of Jak2 Tyrosine Kinase Is Dependent on Specific Regions in Its Pseudokinase Domain. Mol. Biol. Cell 2003, 14, 1448–1459.
  22. Toms, A.V.; Deshpande, A.; McNally, R.; Jeong, Y.; Rogers, J.M.; Kim, C.U.; Gruner, S.M.; Ficarro, S.B.; A Marto, J.; Sattler, M.; et al. Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat. Struct. Mol. Biol. 2013, 20, 1221–1223.
  23. Lupardus, P.J.; Ultsch, M.; Wallweber, H.; Kohli, P.B.; Johnson, A.R.; Eigenbrot, C. Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc. Natl. Acad. Sci. 2014, 111, 8025–8030.
  24. Ferrao, R.; Lupardus, P.J. The Janus Kinase (JAK) FERM and SH2 Domains: Bringing Specificity to JAK–Receptor Interactions. Front. Endocrinol. 2017, 8, 71.
  25. Staerk, J.; Kallin, A.; Demoulin, J.-B.; Vainchenker, W.; Constantinescu, S.N. JAK1 and Tyk2 Activation by the Homologous Polycythemia Vera JAK2 V617F Mutation. J. Biol. Chem. 2005, 280, 41893–41899.
  26. Baxter, E.J.; Scott, L.M.; Campbell, P.J.; East, C.; Fourouclas, N.; Swanton, S.; Vassiliou, G.; Bench, A.J.; Boyd, E.M.; Curtin, N.; et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005, 365, 1054–1061.
  27. E James, C.; Ugo, V.; Le Couédic, J.-P.; Staerk, J.; Delhommeau, F.; Lacout, C.; Garçon, L.; Raslova, H.; Berger, R.; Bennaceur-Griscelli, A.; et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nat. Cell Biol. 2005, 434, 1144–1148.
  28. Kralovics, R.; Passamonti, F.; Buser, A.S.; Teo, S.-S.; Tiedt, R.; Passweg, J.R.; Tichelli, A.; Cazzola, M.; Skoda, R.C. A Gain-of-Function Mutation ofJAK2in Myeloproliferative Disorders. New Engl. J. Med. 2005, 352, 1779–1790.
  29. Lee, J.W.; Kim, Y.G.; Soung, Y.H.; Han, K.J.; Kim, S.Y.; Rhim, H.; Min, W.S.; Nam, S.W.; Park, W.S.; Yoo, N.J.; et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene 2005, 25, 1434–1436.
  30. Passamonti, F.; Rumi, E.; Pietra, D.; Della Porta, M.G.; Boveri, E.; Pascutto, C.; Vanelli, L.; Arcaini, L.; Burcheri, S.; Malcovati, L.; et al. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood 2006, 107, 3676–3682.
  31. Mascarenhas, J.; Hoffman, R. Ruxolitinib: The First FDA Approved Therapy for the Treatment of Myelofibrosis: Figure 1. Clin. Cancer Res. 2012, 18, 3008–3014.
  32. Vainchenker, W.; Constantinescu, S. JAK/STAT signaling in hematological malignancies. Oncogene 2012, 32, 2601–2613.
  33. Raedler, L.A. Jakafi (Ruxolitinib): First FDA-Approved Medication for the Treatment of Patients with Polycythemia Vera. Am. Health Drug benefits 2015, 8, 75–79.
  34. Skoda, R.C.; Duek, A.; Grisouard, J. Pathogenesis of myeloproliferative neoplasms. Exp. Hematol. 2015, 43, 599–608.
  35. De Noronha, T.R.; Mitne-Neto, M.; Chauffaille, M.D.L. JAK2-mutated acute myeloid leukemia: Comparison of next-generation sequencing (NGS) and single nucleotide polymorphism array (SNPa) findings between two cases. Autops. Case Rep. 2019, 9, e2018084.
  36. Mead, A.J.; Rugless, M.J.; Jacobsen, S.E.W.; Schuh, A. GermlineJAK2Mutation in a Family with Hereditary Thrombocytosis. New Engl. J. Med. 2012, 366, 967–969.
  37. Etheridge, S.L.; Cosgrove, M.E.; Sangkhae, V.; Corbo, L.M.; Roh, M.E.; Seeliger, M.A.; Chan, E.L.; Hitchcock, I.S. A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis. Blood 2014, 123, 1059–1068.
  38. Marty, C.; Saint-Martin, C.; Pecquet, C.; Grosjean, S.; Saliba, J.; Mouton, C.; Leroy, E.; Harutyunyan, A.S.; Abgrall, J.-F.; Favier, R.; et al. Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors. Blood 2014, 123, 1372–1383.
  39. Jeong, E.G.; Kim, M.S.; Nam, H.K.; Min, C.K.; Lee, S.; Chung, Y.J.; Yoo, N.J.; Lee, S.H. Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers. Clin. Cancer Res. 2008, 14, 3716–3721.
  40. Mullighan, C.G.; Zhang, J.; Harvey, R.C.; Collins-Underwood, J.R.; Schulman, B.A.; Phillips, L.A.; Tasian, S.K.; Loh, M.L.; Su, X.; Liu, W.; et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. 2009, 106, 9414–9418.
  41. Bellanger, D.E.; Jacquemin, V.; Chopin, M.; Pierron, G.; A Bernard, O.; Ghysdael, J.; Stern, M.-H. Recurrent JAK1 and JAK3 somatic mutations in T-cell prolymphocytic leukemia. Leukemia 2014, 28, 417–419.
  42. Arulogun, S.O.; Choong, H.-L.; Taylor, D.; Ambrosoli, P.; Magor, G.; Irving, I.M.; Keng, T.-B.; Perkins, A.C. JAK1 somatic mutation in a myeloproliferative neoplasm. Haematologica 2017, 102, e324–e327.
  43. Lee, S.; Park, H.Y.; Kang, S.Y.; Kim, S.J.; Hwang, J.; Lee, S.; Kwak, S.H.; Park, K.S.; Yoo, H.Y.; Kim, W.S.; et al. Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type. Oncotarget 2015, 6, 17764–17776.
  44. Ross, J.A.; Kirken, R.A. Transforming Mutations of Jak3 (A573V and M511I) Show Differential Sensitivity to Selective Jak3 Inhibitors. Clin. Cancer Drugs 2016, 3, 131–137.
  45. Sim, S.H.; Kim, S.; Kim, T.M.; Jeon, Y.K.; Nam, S.J.; Ahn, Y.-O.; Keam, B.; Park, H.H.; Kim, D.-W.; Kim, C.W.; et al. Novel JAK3-Activating Mutations in Extranodal NK/T-Cell Lymphoma, Nasal Type. Am. J. Pathol. 2017, 187, 980–986.
  46. Kiyoi, H.; Yamaji, S.; Kojima, S.; Naoe, T. JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults. Leukemia 2007, 21, 574–576.
  47. Malinge, S.; Ragu, C.; Della-Valle, V.; Pisani, D.; Constantinescu, S.N.; Perez, C.; Villeval, J.-L.; Reinhardt, D.; Landman-Parker, J.; Michaux, L.; et al. Activating mutations in human acute megakaryoblastic leukemia. Blood 2008, 112, 4220–4226.
  48. Yamashita, Y.; Yuan, J.; Suetake, I.; Suzuki, H.; Ishikawa, Y.; Choi, Y.L.; Ueno, T.; Soda, M.; Hamada, T.; Haruta, H.; et al. Array-based genomic resequencing of human leukemia. Oncogene 2010, 29, 3723–3731.
  49. Bains, T.; Heinrich, M.C.; Loriaux, M.M.; Beadling, C.; Nelson, D.; Warrick, A.; Neff, T.L.; Tyner, J.W.; Dunlap, J.; Corless, C.L.; et al. Newly described activating JAK3 mutations in T-cell acute lymphoblastic leukemia. Leukemia 2012, 26, 2144–2146.
  50. Koo, G.C.; Tan, S.Y.; Tang, T.; Poon, S.L.; Allen, G.E.; Tan, L.; Chong, S.C.; Ong, W.S.; Tay, K.; Tao, M.; et al. Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma. Cancer Discov. 2012, 2, 591–597.
  51. Zhang, J.; Ding, L.; Holmfeldt, L.; Wu, G.; Heatley, S.L.; Payne-Turner, D.; Easton, J.; Chen, X.; Wang, J.; Rusch, M.; et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012, 481, 157–163.
  52. Bergmann, A.K.; Schneppenheim, S.; Seifert, M.; Betts, M.J.; Haake, A.; Lopez, C.; Penas, E.M.M.; Vater, I.; Jayne, S.; Dyer, M.J.; et al. Recurrent mutation ofJAK3in T-cell prolymphocytic leukemia. Genes, Chromosom. Cancer 2014, 53, 309–316.
  53. Bouchekioua, A.; Scourzic, L.; De Wever, O.; Zhang, Y.; Cervera, P.; Aline-Fardin, A.; Mercher, T.; Gaulard, P.; Nyga, R.; Jeziorowska, D.; et al. JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. Leukemia 2014, 28, 338–348.
  54. Sanda, T.; Tyner, J.W.; Gutierrez, A.; Ngo, V.N.; Glover, J.; Chang, B.H.; Yost, A.; Ma, W.; Fleischman, A.; Zhou, W.; et al. TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia. Cancer Discov. 2013, 3, 564–577.
  55. Waanders, E.; Scheijen, B.; Jongmans, M.; Venselaar, H.; Van Reijmersdal, S.; Van Dijk, A.; Pastorczak, A.; Weren, R.; Van Der Schoot, C.; Van De Vorst, J.; et al. Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences. Leukemia 2017, 31, 821–828.
  56. Wöss, K.; Simonović, N.; Strobl, B.; Macho-Maschler, S.; Müller, M. TYK2: An Upstream Kinase of STATs in Cancer. Cancers 2019, 11, 1728.
  57. Scott, L.M. The JAK2 exon 12 mutations: A comprehensive review. Am. J. Hematol. 2011, 86, 668–676.
  58. Blombery, P.; Thompson, E.R.; Jones, K.; Arnau, G.M.; Lade, S.; Markham, J.F.; Li, J.; Deva, A.; Johnstone, R.W.; Khot, A.; et al. Whole exome sequencing reveals activating JAK1 and STAT3 mutations in breast implant-associated anaplastic large cell lymphoma anaplastic large cell lymphoma. Haematologica 2016, 101, e387–e390.
  59. Li, Q.; Li, B.; Hu, L.; Ning, H.; Jiang, M.; Wang, D.; Liu, T.; Zhang, B.; Chen, H. Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia. Oncotarget 2017, 8, 34687–34697.
  60. Flex, E.; Petrangeli, V.; Stella, L.; Chiaretti, S.; Hornakova, T.; Knoops, L.; Ariola, C.; Fodale, V.; Clappier, E.; Paoloni, F.; et al. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J. Exp. Med. 2008, 205, 751–758.
  61. Hornakova, T.; Springuel, L.; Devreux, J.; Dusa, A.; Constantinescu, S.N.; Knoops, L.; Renauld, J.-C. Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors. Haematologica 2011, 96, 845–853.
  62. Crescenzo, R.; Abate, F.; Lasorsa, E.; Tabbo’, F.; Gaudiano, M.; Chiesa, N.; Di Giacomo, F.; Spaccarotella, E.; Barbarossa, L.; Ercole, E.; et al. Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma. Cancer Cell 2015, 27, 516–532.
  63. Lesmana, H.; Popescu, M.; Lewis, S.; Sahoo, S.S.; Goodings-Harris, C.; Onciu, M.; Choi, J.K.; Takemoto, C.; Nichols, K.E.; Wlodarski, M. Germline Gain-of-Function JAK3 Mutation in Familial Chronic Lymphoproliferative Disorder of NK Cells. Blood 2020, 136, 9–10.
  64. Klusmann, J.-H.; Reinhardt, D.; Hasle, H.; Kaspers, G.J.; Creutzig, U.; Hählen, K.; Heuvel-Eibrink, M.M.V.D.; Zwaan, C.M. Janus kinase mutations in the development of acute megakaryoblastic leukemia in children with and without Down’s syndrome. Leukemia 2007, 21, 1584–1587.
  65. Elliott, N.E.; Cleveland, S.M.; Grann, V.; Janik, J.; Waldmann, T.A.; Davé, U.P. FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. Blood 2011, 118, 3911–3921.
  66. Degryse, S.; De Bock, C.E.; Cox, L.; Demeyer, S.; Gielen, O.; Mentens, N.; Jacobs, K.; Geerdens, E.; Gianfelici, V.; Hulselmans, G.; et al. JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model. Blood 2014, 124, 3092–3100.
  67. Haapaniemi, E.M.; Kaustio, M.; Rajala, H.L.M.; Van Adrichem, A.J.; Kainulainen, L.; Glumoff, V.; Doffinger, R.; Kuusanmäki, H.; Heiskanen-Kosma, T.; Trotta, L.; et al. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3. Blood 2015, 125, 639–648.
  68. Shahmarvand, N.; Nagy, A.; Shahryari, J.; Ohgami, R.S. Mutations in the signal transducer and activator of transcription family of genes in cancer. Cancer Sci. 2018, 109, 926–933.
  69. De Araujo, E.D.; Orlova, A.; Neubauer, H.A.; Bajusz, D.; Seo, H.-S.; Dhe-Paganon, S.; Keserű, G.M.; Moriggl, R.; Gunning, P.T. Structural Implications of STAT3 and STAT5 SH2 Domain Mutations. Cancers 2019, 11, 1757.
  70. Hu, G.; Witzig, T.E.; Gupta, M. A Novel Missense (M206K) STAT3 Mutation in Diffuse Large B Cell Lymphoma Deregulates STAT3 Signaling. PLoS ONE 2013, 8, e67851.
  71. Andersson, E.; Kuusanmäki, H.; Bortoluzzi, S.; Lagström, S.; Parsons, A.; Rajala, H.; Van Adrichem, A.; Eldfors, S.; Olson, T.; Clemente, M.J.; et al. Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia. Leukemia 2015, 30, 1204–1208.
  72. Jerez, A.; Clemente, M.J.; Makishima, H.; Koskela, H.; Leblanc, F.; Ng, K.P.; Olson, T.; Przychodzen, B.; Afable, M.; Gomez-Segui, I.; et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood 2012, 120, 3048–3057.
  73. Koskela, H.L.; Eldfors, S.; Ellonen, P.; Van Adrichem, A.J.; Kuusanmäki, H.; Andersson, E.I.; Lagström, S.; Clemente, M.J.; Olson, T.; Jalkanen, S.E.; et al. SomaticSTAT3Mutations in Large Granular Lymphocytic Leukemia. New Engl. J. Med. 2012, 366, 1905–1913.
  74. Fasan, A.; Kern, W.; Grossmann, V.; Haferlach, C.; Schnittger, S.; Haferlach, T. STAT3 mutations are highly specific for large granular lymphocytic leukemia. Leukemia 2012, 27, 1598–1600.
  75. Küçük, C.; Jiang, B.; Hu, X.; Zhang, W.; Chan, J.K.C.; Xiao, W.; Lack, N.; Alkan, C.; Williams, J.C.; Avery, K.N.; et al. Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nat. Commun. 2015, 6, 1–12.
  76. Bilori, B.; Thota, S.; Clemente, M.J.; Patel, B.; Jerez, A.; Ii, M.A.; Maciejewski, J.P. Tofacitinib as a novel salvage therapy for refractory T-cell large granular lymphocytic leukemia. Leukemia 2015, 29, 2427–2429.
  77. Kuusanmäki, H.; Dufva, O.; Parri, E.; Van Adrichem, A.J.; Rajala, H.; Majumder, M.M.; Yadav, B.; Parsons, A.; Chan, W.C.; Wennerberg, K.; et al. Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling. Oncotarget 2017, 8, 97516–97527.
  78. Matutes, E. The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms. Int. J. Lab. Hematol. 2018, 40, 97–103.
  79. De Araujo, E.D.; Erdogan, F.; Neubauer, H.A.; Meneksedag-Erol, D.; Manaswiyoungkul, P.; Eram, M.S.; Seo, H.-S.; Qadree, A.K.; Israelian, J.; Orlova, A.; et al. Structural and functional consequences of the STAT5BN642H driver mutation. Nat. Commun. 2019, 10, 1–15.
  80. Pham, H.T.T.; Maurer, B.; Prchal-Murphy, M.; Grausenburger, R.; Grundschober, E.; Javaheri, T.; Nivarthi, H.; Boersma, A.; Kolbe, T.; Elabd, M.; et al. STAT5BN642H is a driver mutation for T cell neoplasia. J. Clin. Investig. 2017, 128, 387–401.
  81. Klein, K.; Witalisz-Siepracka, A.; Maurer, B.; Prinz, D.; Heller, G.; Leidenfrost, N.; Prchal-Murphy, M.; Suske, T.; Moriggl, R.; Sexl, V. STAT5BN642H drives transformation of NKT cells: A novel mouse model for CD56+ T-LGL leukemia. Leukemia 2019, 33, 2336–2340.
  82. Nicolae, A.; Xi, L.; Pittaluga, S.; Abdullaev, Z.; Pack, S.D.; Chen, J.; A Waldmann, T.; Jaffe, E.S.; Raffeld, M. Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas. Leukemia 2014, 28, 2244–2248.
  83. Babushok, D.V.; Perdigones, N.; Perin, J.C.; Olson, T.S.; Ye, W.; Roth, J.J.; Lind, C.; Cattier, C.; Li, Y.; Hartung, H.; et al. Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. Cancer Genet. 2015, 208, 115–128.
  84. Jiang, L.; Gu, Z.-H.; Yan, Z.-X.; Zhao, X.; Xie, Y.-Y.; Zhang, Z.-G.; Pan, C.-M.; Hu, Y.; Cai, C.-P.; Dong, Y.; et al. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nat. Genet. 2015, 47, 1061–1066.
  85. Kiel, M.J.; Velusamy, T.; Rolland, D.; Sahasrabuddhe, A.; Chung, F.; Bailey, N.G.; Schrader, A.; Li, B.; Li, J.Z.; Ozel, A.B.; et al. Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood 2014, 124, 1460–1472.
  86. Kiel, M.J.; Sahasrabuddhe, A.A.; Rolland, D.C.M.; Velusamy, T.; Chung, F.; Schaller, M.; Bailey, N.G.; Betz, B.L.; Miranda, R.N.; Porcu, P.; et al. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK–STAT pathway in Sézary syndrome. Nat. Commun. 2015, 6, 8470.
  87. Ma, X.; Wen, L.; Wu, L.; Wang, Q.; Yao, H.; Wang, Q.; Ma, L.; Chen, S. Rare occurrence of a STAT5B N642H mutation in adult T-cell acute lymphoblastic leukemia. Cancer Genet. 2015, 208, 52–53.
  88. Andersson, E.I.; Tanahashi, T.; Sekiguchi, N.; Gasparini, V.R.; Bortoluzzi, S.; Kawakami, T.; Matsuda, K.; Mitsui, T.; Eldfors, S.; Bortoluzzi, S.; et al. High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia. Blood 2016, 128, 2465–2468.
  89. Nairismägi, M.-L.; Tan, J.; Lim, J.Q.; Nagarajan, S.; Ng, C.C.Y.; Rajasegaran, V.; Huang, D.; Lim, W.K.; Laurensia, Y.; Wijaya, G.C.; et al. JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma. Leukemia 2016, 30, 1311–1319.
  90. Gao, L.-M.; Zhao, S.; Liu, W.-P.; Zhang, W.-Y.; Li, G.-D.; Küçük, C.; Hu, X.-Z.; Chan, W.C.; Tang, Y.; Ding, W.-S.; et al. Clinicopathologic Characterization of Aggressive Natural Killer Cell Leukemia Involving Different Tissue Sites. Am. J. Surg. Pathol. 2016, 40, 836–846.
  91. Teramo, A.; Barilà, G.; Calabretto, G.; Ercolin, C.; Lamy, T.; Moignet, A.; Roussel, M.; Pastoret, C.; Leoncin, M.; Gattazzo, C.; et al. STAT3 mutation impacts biological and clinical features of T-LGL leukemia. Oncotarget 2017, 8, 61876–61889.
  92. Ma, C.A.; Xi, L.; Cauff, B.; DeZure, A.; Freeman, A.F.; Hambleton, S.; Kleiner, G.; Leahy, T.R.; O’Sullivan, M.; Makiya, M.; et al. Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood 2017, 129, 650–653.
  93. Dufva, O.; Kankainen, M.; Kelkka, T.; Sekiguchi, N.; Awad, S.A.; Eldfors, S.; Yadav, B.; Kuusanmäki, H.; Malani, D.; I Andersson, E.; et al. Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target. Nat. Commun. 2018, 9, 1–12.
  94. Luo, Q.; Shen, J.; Yang, Y.; Tang, H.; Shi, M.; Liu, J.; Liu, Z.; Shi, X.; Yi, Y. CSF3RT618I,ASXL1G942 fs andSTAT5BN642H trimutation co-contribute to a rare chronic neutrophilic leukaemia manifested by rapidly progressive leucocytosis, severe infections, persistent fever and deep venous thrombosis. Br. J. Haematol. 2016, 180, 892–894.
  95. Huang, L.; Liu, D.; Wang, N.; Ling, S.; Tang, Y.; Wu, J.; Hao, L.; Luo, H.; Hu, X.; Sheng, L.; et al. Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia. Cell Res. 2017, 28, 172–186.
  96. Song, T.L.; Nairismägi, M.-L.; Laurensia, Y.; Lim, J.-Q.; Tan, J.; Li, Z.-M.; Pang, W.-L.; Kizhakeyil, A.; Wijaya, G.-C.; Huang, D.; et al. Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood 2018, 132, 1146–1158.
  97. Cross, N.C.P.; Hoade, Y.; Tapper, W.J.; Carreno-Tarragona, G.; Fanelli, T.; Jawhar, M.; Naumann, N.; Pieniak, I.; Lübke, J.; Ali, S.; et al. Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia 2018, 33, 415–425.
  98. Govaerts, I.; Jacobs, K.; Vandepoel, R.; Cools, J. JAK/STAT Pathway Mutations in T-ALL, Including the STAT5B N642H Mutation, are Sensitive to JAK1/JAK3 Inhibitors. HemaSphere 2019, 3, e313.
  99. Rajala, H.L.M.; Porkka, K.; Maciejewski, J.P.; Loughran, T.P.; Mustjoki, S. Uncovering the pathogenesis of large granular lymphocytic leukemia—novel STAT3 and STAT5b mutations. Ann. Med. 2014, 46, 114–122.
  100. Rajala, H.L.M.; Eldfors, S.; Kuusanmäki, H.; Van Adrichem, A.J.; Olson, T.; Lagström, S.; Andersson, E.I.; Jerez, A.; Clemente, M.J.; Yan, Y.; et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 2013, 121, 4541–4550.
  101. Bandapalli, O.R.; Schuessele, S.; Kunz, J.B.; Rausch, T.; Stütz, A.M.; Tal, N.; Geron, I.; Gershman, N.; Izraeli, S.; Eilers, J.; et al. The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse. Haematologica 2014, 99, e188–e192.
  102. Kontro, M.; Kuusanmäki, H.; Eldfors, S.; Burmeister, T.; Andersson, E.I.; Bruserud, O.; Brümmendorf, T.H.; Edgren, H.; Gjertsen, B.T.; Italaremes, M.; et al. Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia. Leukemia 2014, 28, 1738–1742.
  103. Ritz, O.; Guiter, C.; Castellano, F.; Dorsch, K.; Melzner, J.; Jais, J.-P.; Dubois, G.; Gaulard, P.; Möller, P.; Leroy, K. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood 2009, 114, 1236–1242.
  104. Yildiz, M.; Li, H.; Bernard, D.; Amin, N.A.; Ouillette, P.; Jones, S.; Saiya-Cork, K.; Parkin, B.; Jacobi, K.; Shedden, K.; et al. Activating STAT6 mutations in follicular lymphoma. Blood 2015, 125, 668–679.
  105. Morin, R.D.; Assouline, S.; Alcaide, M.; Mohajeri, A.; Johnston, R.L.; Chong, L.; Grewal, J.; Yu, S.; Fornika, D.; Bushell, K.; et al. Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas. Clin. Cancer Res. 2016, 22, 2290–2300.
  106. Tiacci, E.; Ladewig, E.; Schiavoni, G.; Penson, A.; Fortini, E.; Pettirossi, V.; Wang, Y.; Rosseto, A.; Venanzi, A.; Vlasevska, S.; et al. Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood 2018, 131, 2454–2465.
  107. O’Shea, J.J.; Schwartz, D.M.; Villarino, A.; Gadina, M.; McInnes, I.B.; Laurence, A. The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention. Annu. Rev. Med. 2015, 66, 311–328.
  108. Levine, R.L.; Wadleigh, M.; Cools, J.; Ebert, B.L.; Wernig, G.; Huntly, B.J.; Boggon, T.J.; Wlodarska, I.; Clark, J.J.; Moore, S.; et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005, 7, 387–397.
  109. Helbig, G. Classical Philadelphia-negative myeloproliferative neoplasms: Focus on mutations and JAK2 inhibitors. Med Oncol. 2018, 35, 119.
  110. Lorenzini, T.; Dotta, L.; Giacomelli, M.; Vairo, D.; Badolato, R. STAT mutations as program switchers: Turning primary immunodeficiencies into autoimmune diseases. J. Leukoc. Biol. 2016, 101, 29–38.
  111. Kanai, T.; Jenks, J.; Nadeau, K.C. The STAT5b Pathway Defect and Autoimmunity. Front. Immunol. 2012, 3, 234.
  112. Karjalainen, A.; Shoebridge, S.; Krunic, M.; Simonović, N.; Tebb, G.; Macho-Maschler, S.; Strobl, B.; Müller, M. TYK2 in Tumor Immunosurveillance. Cancers 2020, 12, 150.
  113. Hambleton, S.; Goodbourn, S.; Young, D.F.; Dickinson, P.; Mohamad, S.M.B.; Valappil, M.; McGovern, N.; Cant, A.J.; Hackett, S.J.; Ghazal, P.; et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc. Natl. Acad. Sci. 2013, 110, 3053–3058.
  114. Freij, B.J.; Hanrath, A.T.; Chen, R.; Hambleton, S.; Duncan, C.J.A. Life-Threatening Influenza, Hemophagocytic Lymphohistiocytosis and Probable Vaccine-Strain Varicella in a Novel Case of Homozygous STAT2 Deficiency. Front. Immunol. 2021, 11, 11.
  115. Schimke, L.F.; Hibbard, J.; Martinez-Barricarte, R.; Khan, T.A.; Cavalcante, R.D.S.; Junior, E.B.D.O.; França, T.T.; Iqbal, A.; Yamamoto, G.; Arslanian, C.; et al. Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-γ Immunity. J. Infect. Dis. 2017, 216, 1623–1634.
  116. Powell, D.A.; Shubitz, L.F.; Butkiewicz, C.D.; Moale, H.; Trinh, H.T.; Doetschman, T.; Hsu, A.P.; Holland, S.M.; Galgiani, J.N.; Frelinger, J.A. Modeling a Human STAT4 Mutation That Predisposes to Disseminated Coccidioidomycosis in Mice. J. Immunol. 2020, 204 (Suppl. 1).
  117. Okada, S.; Asano, T.; Moriya, K.; Boisson-Dupuis, S.; Kobayashi, M.; Casanova, J.-L.; Puel, A. Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy. J. Clin. Immunol. 2020, 40, 1065–1081.
  118. Kleppe, M.; Spitzer, M.H.; Li, S.; Hill, C.; Dong, L.; Papalexi, E.; De Groote, S.; Bowman, R.L.; Keller, M.; Koppikar, P.; et al. Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis. Cell Stem Cell 2017, 21, 489–501.e7.
  119. Witalisz-Siepracka, A.; Klein, K.; Prinz, D.; Leidenfrost, N.; Schabbauer, G.; Dohnal, A.; Sexl, V. Loss of JAK1 Drives Innate Immune Deficiency. Front. Immunol. 2019, 9, 10.
  120. Park, S.O.; Wamsley, H.L.; Bae, K.; Hu, Z.; Li, X.; Choe, S.-W.; Slayton, W.B.; Oh, S.P.; Wagner, K.-U.; Sayeski, P.P. Conditional Deletion of Jak2 Reveals an Essential Role in Hematopoiesis throughout Mouse Ontogeny: Implications for Jak2 Inhibition in Humans. PLoS ONE 2013, 8, e59675.
  121. Betts, B.C.; Bastian, D.; Iamsawat, S.; Nguyen, H.; Heinrichs, J.L.; Wu, Y.; Daenthanasanmak, A.; Veerapathran, A.; O’Mahony, A.; Walton, K.; et al. Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. Proc. Natl. Acad. Sci. 2018, 115, 1582–1587.
  122. Simonović, N.; Witalisz-Siepracka, A.; Meissl, K.; Lassnig, C.; Reichart, U.; Kolbe, T.; Farlik, M.; Bock, C.; Sexl, V.; Müller, M.; et al. NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity. J. Immunol. 2019, 202, 1724–1734.
  123. Prchal-Murphy, M.; Witalisz-Siepracka, A.; Bednarik, K.T.; Putz, E.M.; Gotthardt, D.; Meissl, K.; Sexl, V.; Müller, M.; Strobl, B. In vivotumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity. OncoImmunology 2015, 4, e1047579.
  124. Stoiber, D.; Kovacic, B.; Schuster, C.; Schellack, C.; Karaghiosoff, M.; Kreibich, R.; Weisz, E.; Artwohl, M.; Kleine, O.C.; Muller, M.; et al. TYK2 is a key regulator of the surveillance of B lymphoid tumors. J. Clin. Investig. 2004, 114, 1650–1658.
  125. Eletto, D.; Burns, S.O.; Angulo, I.; Plagnol, V.; Gilmour, K.C.; Henriquez, F.; Curtis, J.; Gaspar, M.; Nowak, K.; Daza-Cajigal, V.; et al. Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection. Nat. Commun. 2016, 7, 13992.
  126. Rodig, S.J.; A Meraz, M.; White, J.; A Lampe, P.; Riley, J.K.; Arthur, C.D.; King, K.L.; Sheehan, K.C.; Yin, L.; Pennica, D.; et al. Disruption of the Jak1 Gene Demonstrates Obligatory and Nonredundant Roles of the Jaks in Cytokine-Induced Biologic Responses. Cell 1998, 93, 373–383.
  127. Macchi, P.; Villa, A.; Giliani, S.; Sacco, M.G.; Frattini, A.; Porta, F.; Ugazio, A.G.; Johnston, J.A.; Candotti, F.; O’Sheai, J.J.; et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nat. Cell Biol. 1995, 377, 65–68.
  128. Russell, S.M.; Tayebi, N.; Nakajima, H.; Riedy, M.C.; Roberts, J.L.; Aman, M.J.; Migone, T.-S.; Noguchi, M.; Markert, M.L.; Buckley, R.H.; et al. Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development. Science 1995, 270, 797–800.
  129. Frucht, D.M.; Gadina, M.; Jagadeesh, G.J.; Aksentijevich, I.; Takada, K.; Bleesing, J.; Nelson, J.; Muul, L.M.; Perham, G.; Morgan, G.; et al. Unexpected and variable phenotypes in a family with JAK3 deficiency. Genes Immun. 2001, 2, 422–432.
  130. Notarangelo, L.D.; Giliani, S.; Mella, P.; Schumacher, R.F.; Mazza, C.; Savoldi, G.; Rodriguez-Perez, C.; Badolato, R.; Mazzolari, E.; Porta, F.; et al. Combined Immunodeficiencies Due to Defects in Signal Transduction: Defects of the γc-JAK3 Signaling Pathway as a Model. Immunobiology 2000, 202, 106–119.
  131. Robinette, M.L.; Cella, M.; Telliez, J.B.; Ulland, T.K.; Barrow, A.D.; Capuder, K.; Gilfillan, S.; Lin, L.-L.; Notarangelo, L.D.; Colonna, M. Jak3 deficiency blocks innate lymphoid cell development. Mucosal Immunol. 2018, 11, 50–60.
  132. Baird, A.M.; Thomis, D.C.; Berg, L.J. T cell development and activation in Jak3-deficient mice. J. Leukoc. Biol. 1998, 63, 669–677.
  133. Thomis, D.C.; Gurniak, C.B.; Tivol, E.; Sharpe, A.H.; Berg, L.J. Defects in B Lymphocyte Maturation and T Lymphocyte Activation in Mice Lacking Jak3. Science 1995, 270, 794–797.
  134. Kreins, A.Y.; Ciancanelli, M.J.; Okada, S.; Kong, X.-F.; Ramírez-Alejo, N.; Kilic, S.S.; El Baghdadi, J.; Nonoyama, S.; Mahdaviani, S.A.; Ailal, F.; et al. Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. J. Exp. Med. 2015, 212, 1641–1662.
  135. Minegishi, Y.; Saito, M.; Morio, T.; Watanabe, K.; Agematsu, K.; Tsuchiya, S.; Takada, H.; Hara, T.; Kawamura, N.; Ariga, T.; et al. Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity. Immunity 2006, 25, 745–755.
  136. Sarrafzadeh, S.A.; Mahloojirad, M.; Casanova, J.-L.; Badalzadeh, M.; Bustamante, J.; Boisson-Dupuis, S.; Pourpak, Z.; Nourizadeh, M.; Moin, M. A New Patient with Inherited TYK2 Deficiency. J. Clin. Immunol. 2020, 40, 232–235.
  137. Fuchs, S.; Kaiser-Labusch, P.; Bank, J.; Ammann, S.; Kolb-Kokocinski, A.; Edelbusch, C.; Omran, H.; Ehl, S. Tyrosine kinase 2 is not limiting human antiviral type III interferon responses. Eur. J. Immunol. 2016, 46, 2639–2649.
  138. Oyamada, A.; Ikebe, H.; Itsumi, M.; Saiwai, H.; Okada, S.; Shimoda, K.; Iwakura, Y.; Nakayama, K.I.; Iwamoto, Y.; Yoshikai, Y.; et al. Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis. J. Immunol. 2009, 183, 7539–7546.
  139. Chapgier, A.; Boisson-Dupuis, S.; Jouanguy, E.; Vogt, G.; Feinberg, J.; Prochnicka-Chalufour, A.; Casrouge, A.; Yang, K.; Soudais, C.; Fieschi, C.; et al. Novel STAT1 Alleles in Otherwise Healthy Patients with Mycobacterial Disease. PLoS Genet. 2006, 2, e131.
  140. Boisson-Dupuis, S.; Jouanguy, E.; Al-Hajjar, S.; Fieschi, C.; Al-Mohsen, I.Z.; Al-Jumaah, S.; Yang, K.; Chapgier, A.; Eidenschenk, C.; Eid, P.; et al. Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nat. Genet. 2003, 33, 388–391.
  141. Boisson-Dupuis, S.; Dargemont, C.; Fieschi, C.; Thomassin, N.; Rosenzweig, S.; Harris, J.; Holland, S.M.; Schreiber, R.D.; Casanova, J.-L. Impairment of Mycobacterial But Not Viral Immunity by a Germline Human STAT1 Mutation. Science 2001, 293, 300–303.
  142. Chapgier, A.; Kong, X.-F.; Boisson-Dupuis, S.; Jouanguy, E.; Averbuch, D.; Feinberg, J.; Zhang, S.-Y.; Bustamante, J.; Vogt, G.; Lejeune, J.; et al. A partial form of recessive STAT1 deficiency in humans. J. Clin. Investig. 2009, 119, 1502–1514.
  143. Lee, C.-K.; Rao, D.T.; Gertner, R.; Gimeno, R.; Frey, A.B.; Levy, D.E. Distinct Requirements for IFNs and STAT1 in NK Cell Function. J. Immunol. 2000, 165, 3571–3577.
  144. Putz, E.M.; Gotthardt, D.; Hoermann, G.; Csiszar, A.; Wirth, S.; Berger, A.; Straka, E.; Rigler, D.; Wallner, B.; Jamieson, A.; et al. CDK8-Mediated STAT1-S727 Phosphorylation Restrains NK Cell Cytotoxicity and Tumor Surveillance. Cell Rep. 2013, 4, 437–444.
  145. Semper, C.; Leitner, N.R.; Lassnig, C.; Parrini, M.; Mahlakõiv, T.; Rammerstorfer, M.; Lorenz, K.; Rigler, D.; Müller, S.; Kolbe, T.; et al. STAT1 Is Not Dominant Negative and Is Capable of Contributing to Gamma Interferon-Dependent Innate Immunity. Mol. Cell. Biol. 2014, 34, 2235–2248.
  146. Wang, X.; Zhang, R.; Wu, W.; Wang, A.; Wan, Z.; Van De Veerdonk, F.L.; Li, R. New and recurrentSTAT1mutations in seven Chinese patients with chronic mucocutaneous candidiasis. Int. J. Dermatol. 2016, 56, e30–e33.
  147. Toubiana, J.; Okada, S.; Hiller, J.; Oleastro, M.; Gomez, M.L.; Becerra, J.C.A.; Ouachã©E-Chardin, M.; Fouyssac, F.; Girisha, K.M.; Etzioni, A.; et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 2016, 127, 3154–3164.
  148. Ifrim, D.C.; Quintin, J.; Meerstein-Kessel, L.; Plantinga, T.; Joosten, L.A.B.; Van Der Meer, J.W.M.; Van De Veerdonk, F.L.; Netea, M.G. Defective trained immunity in patients with STAT-1-dependent chronic mucocutaneaous candidiasis. Clin. Exp. Immunol. 2015, 181, 434–440.
  149. Zheng, J.; Van De Veerdonk, F.L.; Crossland, K.L.; Smeekens, S.P.; Chan, C.M.; Al Shehri, T.; Abinun, M.; Gennery, A.R.; Mann, J.; Lendrem, D.W.; et al. Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC). Eur. J. Immunol. 2015, 45, 2834–2846.
  150. Tamaura, M.; Satoh-Takayama, N.; Tsumura, M.; Sasaki, T.; Goda, S.; Kageyama, T.; Hayakawa, S.; Kimura, S.; Asano, T.; Nakayama, M.; et al. Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice. Int. Immunol. 2019, 32, 259–272.
  151. Duncan, C.J.A.; Thompson, B.J.; Chen, R.; Rice, G.I.; Gothe, F.; Young, D.F.; Lovell, S.C.; Shuttleworth, V.G.; Brocklebank, V.; Corner, B.; et al. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation inSTAT2. Sci. Immunol. 2019, 4, eaav7501.
  152. Park, C.; Li, S.; Cha, E.; Schindler, C. Immune Response in Stat2 Knockout Mice. Immunity 2000, 13, 795–804.
  153. Pelham, S.J.; Lenthall, H.C.; Deenick, E.K.; Tangye, S.G. Elucidating the effects of disease-causing mutations on STAT3 function in autosomal-dominant hyper-IgE syndrome. J. Allergy Clin. Immunol. 2016, 138, 1210–1213.e5.
  154. De Beaucoudrey, L.; Puel, A.; Filipe-Santos, O.; Cobat, A.; Ghandil, P.; Chrabieh, M.; Feinberg, J.; Von Bernuth, H.; Samarina, A.; Jannière, L.; et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells. J. Exp. Med. 2008, 205, 1543–1550.
  155. Takeda, K.; Noguchi, K.; Shi, W.; Tanaka, T.; Matsumoto, M.; Yoshida, N.; Kishimoto, T.; Akira, S. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. 1997, 94, 3801–3804.
  156. Flanagan, S.E.; Haapaniemi, E.; Russell, M.A.; Caswell, R.C.; Allen, H.L.; De Franco, E.; McDonald, T.J.; Rajala, H.L.M.; Ramelius, A.; Barton, J.; et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat. Genet. 2014, 46, 812–814.
  157. Chitnis, T.; Najafian, N.; Benou, C.; Salama, A.D.; Grusby, M.J.; Sayegh, M.H.; Khoury, S.J. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J. Clin. Investig. 2001, 108, 739–747.
  158. Hwa, V.; Little, B.; Adiyaman, P.; Kofoed, E.M.; Pratt, K.L.; Ocal, G.; Berberoglu, M.; Rosenfeld, R.G. Severe Growth Hormone Insensitivity Resulting from Total Absence of Signal Transducer and Activator of Transcription 5b. J. Clin. Endocrinol. Metab. 2005, 90, 4260–4266.
  159. Kofoed, E.M.; Hwa, V.; Little, B.; Woods, K.A.; Buckway, C.K.; Tsubaki, J.; Pratt, K.L.; Bezrodnik, L.; Jasper, H.; Tepper, A.; et al. Growth Hormone Insensitivity Associated with aSTAT5bMutation. New Engl. J. Med. 2003, 349, 1139–1147.
  160. Bernasconi, A.; Marino, R.; Ribas, A.; Rossi, J.; Ciaccio, M.; Oleastro, M.; Ornani, A.; Paz, R.; Rivarola, M.A.; Zelazko, M.; et al. Characterization of Immunodeficiency in a Patient With Growth Hormone Insensitivity Secondary to a Novel STAT5b Gene Mutation. Pediatrics 2006, 118, e1584–e1592.
  161. Vargas-Hernández, A.; Witalisz-Siepracka, A.; Prchal-Murphy, M.; Klein, K.; Mahapatra, S.; Al-Herz, W.; Mace, E.M.; Carisey, A.; Orange, J.S.; Sexl, V.; et al. Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function. J. Allergy Clin. Immunol. 2020, 145, 345–357.e9.
  162. Imada, K.; Bloom, E.T.; Nakajima, H.; Horvath-Arcidiacono, J.A.; Udy, G.B.; Davey, H.W.; Leonard, W.J. Stat5b Is Essential for Natural Killer Cell–mediated Proliferation and Cytolytic Activity. J. Exp. Med. 1998, 188, 2067–2074.
  163. Villarino, A.V.; Sciumè, G.; Davis, F.P.; Iwata, S.; Zitti, B.; Robinson, G.W.; Hennighausen, L.; Kanno, Y.; O’Shea, J.J. Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells. J. Exp. Med. 2017, 214, 2999–3014.
  164. Villarino, A.; Laurence, A.; Robinson, G.W.; Bonelli, M.; Dema, B.; Afzali, B.; Shih, H.-Y.; Sun, H.-W.; Brooks, S.R.; Hennighausen, L.; et al. Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions. eLife 2016, 5.
  165. Quintás-Cardama, A.; Verstovsek, S. New JAK2 inhibitors for myeloproliferative neoplasms. Expert Opin. Investig. Drugs 2011, 20, 961–972.
  166. Kleppe, M.; Koche, R.; Zou, L.; van Galen, P.; Hill, C.; Dong, L.; De Groote, S.; Papalexi, E.; Somasundara, A.V.H.; Cordner, K.; et al. Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell 2018, 33, 29–43.e7.
  167. Mondet, J.; Hussein, K.; Mossuz, P. Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest. Mediat. Inflamm. 2015, 2015, 1–10.
  168. Kleppe, M.; Kwak, M.; Koppikar, P.; Riester, M.; Keller, M.; Bastian, L.; Hricik, T.; Bhagwat, N.; McKenney, A.S.; Papalexi, E.; et al. JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response. Cancer Discov. 2015, 5, 316–331.
  169. Przepiorka, D.; Luo, L.; Subramaniam, S.; Qiu, J.; Gudi, R.; Cunningham, L.C.; Nie, L.; Leong, R.; Ma, L.; Sheth, C.; et al. FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease. Oncol. 2019, 25, e328–e334.
  170. Harrison, C.N.; on Behalf of the COMFORT-II Investigators; Vannucchi, A.M.; Kiladjian, J.-J.; Al-Ali, H.K.; Gisslinger, H.; Knoops, L.; Cervantes, F.; Jones, M.M.; Sun, K.; et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia 2016, 30, 1701–1707.
  171. Manduzio, P. Ruxolitinib in myelofibrosis: To be or not to be an immune disruptor. Ther. Clin. Risk Manag. 2017, 13, 169–177.
  172. Tremblay, D.; King, A.; Li, L.; Moshier, E.; Coltoff, A.; Koshy, A.; Kremyanskaya, M.; Hoffman, R.; Mauro, M.J.; Rampal, R.K.; et al. Risk factors for infections and secondary malignancies in patients with a myeloproliferative neoplasm treated with ruxolitinib: A dual-center, propensity score-matched analysis. Leuk. Lymphoma 2019, 61, 660–667.
  173. Porpaczy, E.; Tripolt, S.; Hoelbl-Kovacic, A.; Gisslinger, B.; Bago-Horvath, Z.; Casanova-Hevia, E.; Clappier, E.; Decker, T.; Fajmann, S.; Fux, D.A.; et al. Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy. Blood 2018, 132, 694–706.
  174. Rumi, E.; Zibellini, S.; Boveri, E.; Cavalloni, C.; Riboni, R.; Casetti, I.C.; Ciboddo, M.; Trotti, C.; Favaron, C.; Pietra, D.; et al. Ruxolitinib treatment and risk of B-cell lymphomas in myeloproliferative neoplasms. Am. J. Hematol. 2019, 94, E185–E188.
  175. Mora, B.; Rumi, E.; Guglielmelli, P.; Barraco, D.; Maffioli, M.; Rambaldi, A.; Caramella, M.; Komrokji, R.; Gotlib, J.; Kiladjian, J.J.; et al. Second primary malignancies in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 2233 patients. Cancer Med. 2019, 8, 4089–4092.
  176. Maffioli, M.; Giorgino, T.; Mora, B.; Iurlo, A.; Elli, E.; Finazzi, M.C.; Caramella, M.; Rumi, E.; Carraro, M.C.; Polverelli, N.; et al. Second primary malignancies in ruxolitinib-treated myelofibrosis: Real-world evidence from 219 consecutive patients. Blood Adv. 2019, 3, 3196–3200.
  177. Smolen, J.S.; Genovese, M.C.; Takeuchi, T.; Hyslop, D.L.; Macias, W.L.; Rooney, T.; Chen, L.; Dickson, C.L.; Camp, J.R.; Cardillo, T.E.; et al. Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment. J. Rheumatol. 2018, 46, 7–18.
  178. Schönberg, K.; Rudolph, J.; Vonnahme, M.; Yajnanarayana, S.P.; Cornez, I.; Hejazi, M.; Manser, A.R.; Uhrberg, M.; Verbeek, W.; Koschmieder, S.; et al. JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms. Cancer Res. 2015, 75, 2187–2199.
  179. Curran, S.A.; Shyer, J.A.; Angelo, E.T.S.; Talbot, L.R.; Sharma, S.; Chung, D.J.; Heller, G.; Hsu, K.C.; Betts, B.C.; Young, J.W. Human Dendritic Cells Mitigate NK-Cell Dysfunction Mediated by Nonselective JAK1/2 Blockade. Cancer Immunol. Res. 2017, 5, 52–60.
  180. Lucas, M.; Schachterle, W.; Oberle, K.; Aichele, P.; Diefenbach, A. Dendritic Cells Prime Natural Killer Cells by trans-Presenting Interleukin 15. Immunity 2007, 26, 503–517.
  181. Heine, A.; Held, S.A.E.; Daecke, S.N.; Wallner, S.; Yajnanarayana, S.P.; Kurts, C.; Wolf, D.; Brossart, P. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013, 122, 1192–1202.
  182. Rudolph, J.; Heine, A.; Quast, T.; Kolanus, W.; Trebicka, J.; Brossart, P.; Wolf, D. The JAK inhibitor ruxolitinib impairs dendritic cell migration via off-target inhibition of ROCK. Leukemia 2016, 30, 2119–2123.
  183. Yajnanarayana, S.P.; Stübig, T.; Cornez, I.; Alchalby, H.; Schönberg, K.; Rudolph, J.; Triviai, I.; Wolschke, C.; Heine, A.; Brossart, P.; et al. JAK1/2 inhibition impairs T cell functionin vitroand in patients with myeloproliferative neoplasms. Br. J. Haematol. 2015, 169, 824–833.
  184. Keohane, C.; Kordasti, S.Y.; Seidl, T.; Abellan, P.P.; Thomas, N.S.B.; Harrison, C.N.; McLornan, D.P.; Mufti, G.J. JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells. Br. J. Haematol. 2015, 171, 60–73.
  185. Massa, M.L.; Rosti, V.; Campanelli, R.; Fois, G.; Barosi, G. Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib. Leukemia 2014, 28, 449–451.
  186. Spoerl, S.; Mathew, N.R.; Bscheider, M.; Schmitt-Graeff, A.; Chen, S.; Mueller, T.; Verbeek, M.; Fischer, J.; Otten, V.; Schmickl, M.; et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014, 123, 3832–3842.
  187. Sørensen, A.L.; Bjørn, M.E.; Riley, C.H.; Holmstrøm, M.; Andersen, M.H.; Svane, I.M.; Mikkelsen, S.U.; Skov, V.; Kjaer, L.; Hasselbalch, H.C.; et al. B-cell frequencies and immunoregulatory phenotypes in myeloproliferative neoplasms: Influence of ruxolitinib, interferon-α2, or combination treatment. Eur. J. Haematol. 2019, 103, 351–361.
  188. Fleischmann, R.; Kremer, J.; Cush, J.; Schulze-Koops, H.; Connell, C.A.; Bradley, J.D.; Gruben, D.; Wallenstein, G.V.; Zwillich, S.H.; Kanik, K.S. Placebo-Controlled Trial of Tofacitinib Monotherapy in Rheumatoid Arthritis. New Engl. J. Med. 2012, 367, 495–507.
  189. Kontzias, A.; Kotlyar, A.; Laurence, A.; Changelian, P.; O’Shea, J.J. Jakinibs: A new class of kinase inhibitors in cancer and autoimmune disease. Curr. Opin. Pharmacol. 2012, 12, 464–470.
  190. Degryse, S.; Cools, J. JAK kinase inhibitors for the treatment of acute lymphoblastic leukemia. J. Hematol. Oncol. 2015, 8, 1–5.
  191. Ghoreschi, K.; Jesson, M.I.; Li, X.; Lee, J.L.; Ghosh, S.; Alsup, J.W.; Warner, J.D.; Tanaka, M.; Steward-Tharp, S.M.; Gadina, M.; et al. Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550). J. Immunol. 2011, 186, 4234–4243.
  192. Migita, K.; Miyashita, T.; Izumi, Y.; Koga, T.; Komori, A.; Maeda, Y.; Jiuchi, Y.; Aiba, Y.; Yamasaki, S.; Kawakami, A.; et al. Inhibitory effects of the JAK inhibitor CP690,550 on human CD4+ T lymphocyte cytokine production. BMC Immunol. 2011, 12, 51.
  193. Sonomoto, K.; Yamaoka, K.; Kubo, S.; Hirata, S.; Fukuyo, S.; Maeshima, K.; Suzuki, K.; Saito, K.; Tanaka, Y. Effects of tofacitinib on lymphocytes in rheumatoid arthritis: Relation to efficacy and infectious adverse events. Rheumatology 2014, 53, 914–918.
  194. A Hodge, J.; Kawabata, T.T.; Krishnaswami, S.; Clark, J.D.; Telliez, J.-B.; E Dowty, M.; Menon, S.; Lamba, M.; Zwillich, S. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin. Exp. Rheumatol. 2016, 34, 318–328.
  195. Conklyn, M.; Andresen, C.; Changelian, P.; Kudlacz, E. The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. J. Leukoc. Biol. 2004, 76, 1248–1255.
  196. Kudlacz, E.; Perry, B.; Sawyer, P.; Conklyn, M.; McCurdy, S.; Brissette, W.; And, M.F.; Changelian, P. The Novel JAK-3 Inhibitor CP-690550 Is a Potent Immunosuppressive Agent in Various Murine Models. Arab. Archaeol. Epigr. 2004, 4, 51–57.
  197. Shimaoka, H.; Takeno, S.; Maki, K.; Sasaki, T.; Hasegawa, S.; Yamashita, Y. A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer. Oncol. Lett. 2017, 14, 3019–3027.
  198. Vian, L.; Le, M.T.; Gazaniga, N.; Kieltyka, J.; Liu, C.; Pietropaolo, G.; Dell’Orso, S.; Brooks, S.R.; Furumoto, Y.; Thomas, C.J.; et al. JAK Inhibition Differentially Affects NK Cell and ILC1 Homeostasis. Front. Immunol. 2019, 10, 2972.
  199. Rochman, Y.; Spolski, R.; Leonard, W.J. New insights into the regulation of T cells by γc family cytokines. Nat. Rev. Immunol. 2009, 9, 480–490.
  200. Meazza, R.; Azzarone, B.; Orengo, A.M.; Ferrini, S. Role of Common-Gamma Chain Cytokines in NK Cell Development and Function: Perspectives for Immunotherapy. J. Biomed. Biotechnol. 2011, 2011, 1–16.
  201. Marçais, A.; Viel, S.; Grau, M.; Henry, T.; Marvel, J.; Walzer, T. Regulation of Mouse NK Cell Development and Function by Cytokines. Front. Immunol. 2013, 4, 450.
  202. Changelian, P.S.; Flanagan, M.E.; Ball, D.J.; Kent, C.R.; Magnuson, K.S.; Martin, W.H.; Rizzuti, B.J.; Sawyer, P.S.; Perry, B.D.; Brissette, W.H.; et al. Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor. Science 2003, 302, 875–878.
  203. Van Vollenhoven, R.; Tanaka, Y.; Lamba, M.; Collinge, M.; Hendrikx, T.; Hirose, T.; Toyoizumi, S.; Hazra, A.; Krishnaswami, S. THU0178 Relationship Between NK Cell Count and Important Safety Events in Rheumatoid Arthritis Patients Treated with Tofacitinib. Ann. Rheum. Dis. 2015, 74, 258.3–259.
  204. Van Vollenhoven, R.; Choy, E.; Lee, E.; Hazra, A.; Anisfeld, A.; Lazariciu, I.; Biswas, P.; Lamba, M.; Menon, S.; Hodge, J.; et al. THU0199 Tofacitinib, An Oral Janus Kinase Inhibitor, in The Treatment of Rheumatoid Arthritis: Changes in Lymphocytes and Lymphocyte Subset Counts and Reversibility after Up To 8 Years of Tofacitinib Treatment. Ann. Rheum. Dis. 2016, 75, 258.
  205. Van Vollenhoven, R.; Lee, E.B.; Strengholt, S.; Mojcik, C.; Valdez, H.; Krishnaswami, S.; Biswas, P.; Lazariciu, I.; Hazra, A.; Clark, J.D.; et al. Evaluation of the Short-, Mid-, and Long-Term Effects of Tofacitinib on Lymphocytes in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2019, 71, 685–695.
  206. Weinhold, K.J.; Bukowski, J.F.; Brennan, T.V.; Noveck, R.J.; Staats, J.S.; Lin, L.; Stempora, L.; Hammond, C.; Wouters, A.; Mojcik, C.F.; et al. Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers. Clin. Immunol. 2018, 191, 10–20.
  207. Angelini, J.; Talotta, R.; Roncato, R.; Fornasier, G.; Barbiero, G.; Cin, L.D.; Brancati, S.; Scaglione, F. JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future. Biomolecules 2020, 10, 1002.
  208. Nocturne, G.; Pascaud, J.; Ly, B.; Tahmasebi, F.; Mariette, X. JAK inhibitors alter NK cell functions and may impair immunosurveillance against lymphomagenesis. Cell. Mol. Immunol. 2020, 17, 552–553.
  209. Kubo, S.; Yamaoka, K.; Kondo, M.; Yamagata, K.; Zhao, J.; Iwata, S.; Tanaka, Y. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann. Rheum. Dis. 2013, 73, 2192–2198.
  210. Sewgobind, V.D.K.D.; Quaedackers, M.E.; Van Der Laan, L.J.W.; Kraaijeveld, R.; Korevaar, S.S.; Chan, G.; Weimar, W.; Baan, C.C. The Jak Inhibitor CP-690,550 Preserves the Function of CD4+CD25brightFoxP3+ Regulatory T Cells and Inhibits Effector T Cells. Arab. Archaeol. Epigr. 2010, 10, 1785–1795.
  211. Meyer, A.; Wittekind, P.S.; Kotschenreuther, K.; Schiller, J.; Von Tresckow, J.; Haak, T.H.; Kofler, D.M. Regulatory T cell frequencies in patients with rheumatoid arthritis are increased by conventional and biological DMARDs but not by JAK inhibitors. Ann. Rheum. Dis. 2019.
  212. Rizzi, M.; Lorenzetti, R.; Fischer, K.; Staniek, J.; Janowska, I.; Troilo, A.; Strohmeier, V.; Erlacher, M.; Kunze, M.; Bannert, B.; et al. Impact of tofacitinib treatment on human B-cells in vitro and in vivo. J. Autoimmun. 2017, 77, 55–66.
  213. Mariette, X.; Chen, C.; Biswas, P.; Kwok, K.; Boy, M.G. Lymphoma in the Tofacitinib Rheumatoid Arthritis Clinical Development Program. Arthritis Rheum. 2018, 70, 685–694.
  214. PFIZER press release. Available online: (accessed on 1 April 2021).
  215. Talpaz, M.; Kiladjian, J.-J. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis. Leukemia 2021, 35, 1–17.
  216. Kim, W.S.; Kim, M.J.; Kim, D.O.; Byun, J.-E.; Huy, H.; Song, H.Y.; Park, Y.-J.; Kim, T.-D.; Yoon, S.R.; Choi, E.-J.; et al. Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity. Sci. Rep. 2017, 7, 46153.
  217. Betts, B.C.; Abdel-Wahab, O.; Curran, S.A.; Angelo, E.T.S.; Koppikar, P.; Heller, G.; Levine, R.L.; Young, J.W. Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen. Blood 2011, 118, 5330–5339.
  218. Mesa, R.A.; Kiladjian, J.-J.; Catalano, J.V.; Devos, T.; Egyed, M.; Hellmann, A.; McLornan, D.; Shimoda, K.; Winton, E.F.; Deng, W.; et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naïve Patients With Myelofibrosis. J. Clin. Oncol. 2017, 35, 3844–3850.
  219. Patel, A.A.; Odenike, O. The Next Generation of JAK Inhibitors: An Update on Fedratinib, Momelotonib, and Pacritinib. Curr. Hematol. Malign- Rep. 2020, 15, 409–418.
  220. Singer, J.W.; Al-Fayoumi, S.; Taylor, J.; Velichko, S.; O’Mahony, A. Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLoS ONE 2019, 14, e0222944.
  221. Singer, J.W.; Al-Fayoumi, S.; Ma, H.; Komrokji, R.S.; Mesa, R.; Verstovsek, S. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J. Exp. Pharmacol. 2016, ume 8, 11–19.
  222. Hosseini, M.M.; Kurtz, S.E.; Abdelhamed, S.; Mahmood, S.; Davare, M.A.; Kaempf, A.; Elferich, J.; McDermott, J.E.; Liu, T.; Payne, S.H.; et al. Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia 2018, 32, 2374–2387.
  223. Pidala, J.; Walton, K.; Elmariah, H.; Kim, J.; Mishra, A.; Bejanyan, N.; Nishihori, T.; Khimani, F.; Perez, L.; Faramand, R.G.; et al. Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD Prevention after Allogeneic Hematopoietic Cell Transplantation: Preclinical and Phase I Trial Results. Clin. Cancer Res. 2021, 27, 2712–2722.
  224. Covington, M.; He, X.; Scuron, M.; Li, J.; Collins, R.; Juvekar, A.; Shin, N.; Favata, M.; Gallagher, K.; Sarah, S.; et al. Preclinical characterization of itacitinib (INCB039110), a novel selective inhibitor of JAK1, for the treatment of inflammatory diseases. Eur. J. Pharmacol. 2020, 885, 173505.
  225. Murray, P.J. The JAK-STAT Signaling Pathway: Input and Output Integration. J. Immunol. 2007, 178, 2623–2629.
  226. Huarte, E.; O’Connor, R.S.; Peel, M.T.; Nunez-Cruz, S.; Leferovich, J.; Juvekar, A.; Yang, Y.-O.; Truong, L.; Huang, T.; Naim, A.; et al. Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy. Clin. Cancer Res. 2020, 26, 6299–6309.
  227. Juvekar, A.; Ruggeri, B.; Condon, S.; Borkowski, A.; Huber, R.; Smith, P. Itacitinib, a JAK1 Selective Inhibitor Preserves Graft-Versus-Leukemia (GVL), Enhances Survival and Is Highly Efficacious in a MHC-Mismatched Mouse Model of Acute GvHD. Blood 2018, 132, 4522.
  228. Schroeder, M.A.; Khoury, H.J.; Jagasia, M.; Ali, H.; Schiller, G.J.; Staser, K.; Choi, J.; Gehrs, L.; Arbushites, M.C.; Yan, Y.; et al. A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease. Blood Adv. 2020, 4, 1656–1669.
  229. Luchi, M.; Fidelus-Gort, R.; Douglas, D.; Zhang, H.; Flores, R.; Newton, R.; Scherle, P.; Yeleswaram, S.; Chen, X.; Sandor, V.A. Randomized, Dose-Ranging, Placebo-Controlled, 84-Day Study Of INCB039110, a Selective Janus Kinase-1 Inhibitor, In Pa-tients With Active Rheumatoid Arthritis - ACR Meeting Abstracts. Arthritis Rheum 2013, 65 (Suppl. 10), 1797.
  230. Norman, P. Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin. Investig. Drugs 2014, 23, 1067–1077.
  231. Bissonnette, R.; Luchi, M.; Fidelus-Gort, R.; Jackson, S.; Zhang, H.; Flores, R.; Newton, R.; Scherle, P.; Yeleswaram, S.; Chen, X.; et al. A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis. J. Dermatol. Treat. 2015, 27, 332–338.
  232. Banerjee, S.; Biehl, A.; Gadina, M.; Hasni, S.; Schwartz, D.M. JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs 2017, 77, 521–546.
  233. Zhang, M.; Griner, L.A.M.; Ju, W.; Duveau, D.Y.; Guha, R.; Petrus, M.N.; Wen, B.; Maeda, M.; Shinn, P.; Ferrer, M.; et al. Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia. Proc. Natl. Acad. Sci. 2015, 112, 12480–12485.
  234. Waldmann, T.A. JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics. Mol. Cell. Endocrinol. 2017, 451, 66–70.
  235. Senkevitch, E.; Li, W.; Hixon, J.A.; Andrews, C.; Cramer, S.D.; Pauly, G.; Back, T.; Czarra, K.; Durum, S.K. Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations. Oncotarget 2018, 9, 22605–22617.
  236. Shouse, G.; Nikolaenko, L. Targeting the JAK/STAT Pathway in T Cell Lymphoproliferative Disorders. Curr. Hematol. Malign- Rep. 2019, 14, 570–576.
  237. Hee, Y.T.; Yan, J.; Nizetic, D.; Chng, W.-J. LEE011 and ruxolitinib: A synergistic drug combination for natural killer/T-cell lymphoma (NKTCL). Oncotarget 2018, 9, 31832–31841.
  238. Mondéjar, R.; Pérez, C.; Onaindía, A.; Martínez, N.; González-Rincón, J.; Pisonero, H.; Vaque, J.P.; Cereceda, L.; Santibañez, M.; Sánchez-Beato, M.; et al. Molecular basis of targeted therapy in T/NK-cell lymphoma/leukemia: A comprehensive genomic and immunohistochemical analysis of a panel of 33 cell lines. PLoS ONE 2017, 12, e0177524.
  239. Neste, E.V.D.; André, M.; Gastinne, T.; Stamatoullas, A.; Haioun, C.; Belhabri, A.; Reman, O.; Casasnovas, O.; Ghesquieres, H.; Verhoef, G.; et al. A phase II study of the oral JAK1/JAK2 inhibitor ruxolitinib in advanced relapsed/refractory Hodgkin lymphoma. Haematologica 2018, 103, 840–848.
  240. Moskowitz, A.J.; Ghione, P.; Jacobsen, E.D.; Ruan, J.; Schatz, J.H.; Noor, S.; Myskowski, P.; Hancock, A.H.; Davey, M.T.; Obadi, O.; et al. Final Results of a Phase II Biomarker-Driven Study of Ruxolitinib in Relapsed and Refractory T-Cell Lymphoma. Blood 2019, 134, 4019.
  241. Mulvey, E.; Ruan, J. Biomarker-driven management strategies for peripheral T cell lymphoma. J. Hematol. Oncol. 2020, 13, 1–20.
  242. Karagianni, F.; Piperi, C.; Mpakou, V.; Spathis, A.; Foukas, P.G.; Dalamaga, M.; Pappa, V.; Papadavid, E. Ruxolitinib with resminostat exert synergistic antitumor effects in Cutaneous T-cell Lymphoma. PLoS ONE 2021, 16, e0248298.
  243. Braun, T.; Von Jan, J.; Wahnschaffe, L.; Herling, M. Advances and Perspectives in the Treatment of T-PLL. Curr. Hematol. Malign- Rep. 2020, 15, 113–124.
  244. Ando, S.; Kawada, J.-I.; Watanabe, T.; Suzuki, M.; Sato, Y.; Torii, Y.; Asai, M.; Goshima, F.; Murata, T.; Shimizu, N.; et al. Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells. Oncotarget 2016, 7, 76793–76805.
  245. Wei, B.M.; Koshy, N.; Van Besien, K.; Inghirami, G.; Horwitz, S.M. Refractory T-Cell Prolymphocytic Leukemia with JAK3 Mutation: In Vitro and Clinical Synergy of Tofacitinib and Ruxolitinib. Blood 2015, 126, 5486.
  246. Gomez-Arteaga, A.; Margolskee, E.; Wei, M.T.; Van Besien, K.; Inghirami, G.; Horwitz, S. Combined use of tofacitinib (pan-JAK inhibitor) and ruxolitinib (a JAK1/2 inhibitor) for refractory T-cell prolymphocytic leukemia (T-PLL) with a JAK3 mutation. Leuk. Lymphoma 2019, 60, 1626–1631.
  247. Lindahl, L.M.; Fredholm, S.; Joseph, C.; Nielsen, B.S.; Jønson, L.; Willerslev-Olsen, A.; Gluud, M.; Blümel, E.; Petersen, D.L.; Sibbesen, N.; et al. STAT5 induces miR-21 expression in cutaneous T cell lymphoma. Oncotarget 2016, 7, 45730–45744.
  248. Cabannes, A.; Schmidt, A.; Brissot, E.; Balsat, M.; Maury, S.; Isnard, F.; Chevallier, P.; Cacheux, V.; Cluzeau, T.; Graux, C.; et al. The Combination of Venetoclax and Tofacitinib Induced Hematological Responses in Patients with Relapse/ Refractory T-ALL with BCL2 Expression and Surface IL7R Expression or IL7R-Pathway Mutations (On behalf of the GRAALL). Blood 2019, 134, 1339.
  249. Wong, J.; Wall, M.; Corboy, G.P.; Taubenheim, N.; Gregory, G.P.; Opat, S.; Shortt, J. Failure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations. Mol. Case Stud. 2020, 6, a004994.
  250. Zhang, R.; Shah, M.V.; Loughran, T.P. The root of many evils: Indolent large granular lymphocyte leukaemia and associated disorders. Hematol. Oncol. 2009, 28, 105–117.
  251. Lamy, T.; Loughran, J.T.P. How I treat LGL leukemia. Blood 2011, 117, 2764–2774.
  252. Shah, M.V.; Hook, C.C.; Call, T.G.; Go, R.S. A population-based study of large granular lymphocyte leukemia. Blood Cancer J. 2016, 6, e455.
  253. Lamy, T.; Moignet, A.; Loughran, T.P. LGL leukemia: From pathogenesis to treatment. Blood 2017, 129, 1082–1094.
  254. Firestein, G.S. Evolving concepts of rheumatoid arthritis. Nat. Cell Biol. 2003, 423, 356–361.
  255. Liu, X.; Loughran, T.P. The spectrum of large granular lymphocyte leukemia and Feltyʼs syndrome. Curr. Opin. Hematol. 2011, 18, 254–259.
  256. Bockorny, B.; Dasanu, C.A. Autoimmune Manifestations in Large Granular Lymphocyte Leukemia. Clin. Lymphoma Myeloma Leuk. 2012, 12, 400–405.
  257. Poullot, E.; Zambello, R.; Leblanc, F.; Bareau, B.; De March, E.; Roussel, M.; Boulland, M.L.; Houot, R.; Renault, A.; Fest, T.; et al. Chronic natural killer lymphoproliferative disorders: Characteristics of an international cohort of 70 patients. Ann. Oncol. 2014, 25, 2030–2035.
  258. Moignet, A.; Lamy, T. Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Am. Soc. Clin. Oncol. Educ. Book 2018, 38, 616–625.
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Agnieszka Witalisz-Siepracka
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