Submitted Successfully!
Thank you for your contribution! You can also upload a video entry related to this topic through the link below: https://encyclopedia.pub/user/video_add?id=23424
Check Note
2000/2000
Ver. Summary Created by Modification Content Size Created at Operation
1 -- 3347 2022-05-26 12:51:48 |
2 format -10 word(s) 3337 2022-05-27 03:35:44 |
Gene Mutations in Systemic Mastocytosis
Edit
Upload a video
Systemic mastocytosis (SM) is a rare hematologic disease characterized by an abnormal expansion and accumulation of pathological mast cells (MCs) in skin and/or other several extracutaneous tissues such as bone marrow (BM) and the gastro-intestinal tract. Currently, SM is divided into five different diagnostic subtypes according to the World Health Organization (WHO) 2016 classification. These include indolent SM (ISM), smouldering SM (SSM), aggressive SM (ASM), SM with associated haematological neoplasms (SM-AHN) and MC leukaemia (MCL). Additionally, the inclusion of two new subtypes of SM into the classification of the disease is currently under consideration: a variant of ISM known as BM mastocytosis (BMM), which is characterized by a low BM MC burden in the absence of skin lesions, and a very rare (<5%) variant of mastocytosis, which shows tumour mast cells (MCs) with a well-differentiated morphology together with a CD25 CD2 immunophenotype and unique clinical, biological and molecular features, termed well-differentiated SM (WDSM). From a prognostic point of view, all these diagnostic subtypes of SM can be grouped into (i) non-advanced forms of SM (Non-AdvSM), which include BMM, ISM and SSM, typically characterized by a more stable and indolent course of the disease and a life expectancy similar or close to that of a sex- and age-matched population; and (ii) advanced SM (AdvSM) including ASM, SM-AHN and MCL, which typically display an adverse prognosis associated with a significantly shortened life expectancy requiring cytoreductive therapy. Despite this, some ISM patients (<5%) can eventually evolve to SSM and AdvSM. Conversely, a small proportion of AdvSM patients may also show a relatively stable disease course over years or even decades.
systemic mastocytosis prognostic mutations KIT D816V ASXL1 DNMT3A
Information
View Times: 132
Revisions: 2 times (View History)
Update Date: 27 May 2022
Table of Contents

    1. KIT Mutations in Systemic Mastocytosis

    The KIT gene is a proto-oncogene encoding for a trans-membrane receptor (mast/stem cell growth factor receptor (KIT)) with tyrosine kinase (TK) activity located on the long arm of human chromosome 4 [1]. When the KIT ligand—stem cell growth factor (SCF)—binds to KIT, conformational changes occur that lead to dimerization of the receptor and its activation by autophosphorylation [2]. Of note, intracellular signalling triggered upon activation of the KIT receptor is key to the normal development of haematopoiesis and the survival of haematopoietic stem cells (HSC) [3]. Except for MCs and some natural killer (NK) cells, KIT is no longer expressed by other mature myeloid and lymphoid haematopoietic cells [4]. In mast cells (MCs), KIT expression remains at high levels throughout maturation [5][6], playing a critical role in MC proliferation, differentiation and survival [2][7]. Therefore, the acquisition of mutations that could impair the normal function of KIT (e.g., activating KIT mutations) has pro-oncogenic effects associated with inhibition of apoptosis and increased MC proliferation and survival [8][9].

    1.1. KIT D816V Mutation

    The D816V mutation of KIT is located at exon 17 within the tyrosine kinase (TK) 2 domain of the KIT gene. This mutation causes constitutive activation of the KIT receptor in the absence of SCF binding and represents the most frequent genetic alteration in SM (>90% of adult SM patients) [2][10]. In fact, constitutive activation of KIT causes preferential differentiation of HSC toward cell lines regulated by KIT expression and signalling (mainly MCs and to a large extent also other myeloid lineages). The fact that MCs are the only haematopoietic cells that express KIT throughout their maturation [5][6] would explain why this KIT-activating mutation induces the expansion and accumulation of pathological MCs in different organs and tissues, as typically observed in SM and other KIT-mutated MC diseases [11]. Of note, the prevalence of the KIT D816V mutation is very similar among adult patients diagnosed with Non-AdvSM and AdvSM [10]. Therefore, the KIT D816V mutation is considered as a (specific) diagnostic marker of SM, regardless of the subtype of the disease, its presence being one of the four minor criteria required by WHO for the diagnosis of SM [12][13][14]. However, the presence of this mutation cannot explain by itself the wide spectrum of disease behaviour observed among SM patients, ranging from stable and even pauci-symptomatic to progressive and even highly-aggressive disease [15].

    1.2. Other KIT Mutations

    Overall, KIT mutations other than KIT D816V can be found in up to 4–5% adults and one third of children with mastocytosis [10]. In adults, these mutations are mostly located at codons 814–822 within exon 17 [10][16][17][18][19][20][21], including several mutant variants at codon 816 [10][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. KIT mutations located outside exon 17 include rare mutations that mostly affect exons 2 [19], 5 [30], 7–11 [19][22][30][36][37][38][39][40][41][42][43][44][45][46][47][48], 13 [19][49] and 18 [19]. Of note, most mutations other than KIT D816V correspond to isolated cases of SM-AHN, MCL or WDSM. Interestingly, MCL patients with KIT mutations other than D816V often lack additional somatic high-risk mutations [36]. Although the vast majority of KIT mutations defined above are acquired (somatic) genetic variants, a few mutations typically located in exons 8 to 10 of KIT (e.g., delD419 [50], S451C [51], K509I [52][53] or F522C [44]) correspond to germinal mutations that frequently show a familial aggregation pattern.
    From a clinical point of view, the exact location of the mutations in the KIT gene is of great relevance, since those mutations that occur within the transmembrane or juxtamembrane domains of the KIT gene (exons 9–11) induce spontaneous receptor dimerization, making pathological MCs sensitive to conventional TK inhibitor therapies (e.g., imatinib) [42][43][44][45][52][54], while KIT mutations involving the catalytic domain (exons 13–18) cause a conformational change of the protein, which confers intrinsic resistance to imatinib and other TK inhibitors commonly used to treat other human tumours [55][56].

    2. Clonal Haematopoiesis in Systemic Mastocytosis

    SM is considered a clonal HSC disease characterized by the expansion and accumulation of neoplastic MCs [57][58][59]. As a neoplasm involving the HSC compartment, the KIT D816V (and other KIT) mutations can be found in both neoplastic MCs and CD34+ BM HSC, as well as in other myeloids (e.g., neutrophils [10][60][61][62], monocytes [10][58][60][61][62], basophils [58][60][62] and/or eosinophils [10][62]) and/or lymphoid (e.g., T and B lymphocytes [10][58][61][62]) cells. In such cases presenting multilineage involvement of haematopoiesis, clonal myeloid (MM) or myeloid plus lymphoid (MML) cells are found, which derive from the expansion and differentiation of D816V-mutated HSCs to different myeloid and/or lymphoid cell lineages [15][63]. Moreover, KIT D816V-mutated BM mesenchymal stem cells (MSCs) are also frequently detected in MML-mutated cases [26][64][65]. Overall, multilineage involvement of haematopoiesis by the KIT D816V mutation is found in virtually all ASM and SSM patients, in around one third of ISM cases and in a small proportion (≤10%) of BMM patients [10][66]. In SM-AHN, the frequency of patients that show a multilineage KIT D816V mutation may vary significantly [26] depending on the specific subtypes of SM and AHN [10]. Thus, KIT D816V-mutated AHN cells have been found in 89% of SM associated with chronic myelomonocytic leukaemia (SM-CMML), while this would only occur in 20% of SM associated with myeloproliferative neoplasms (MPN) and 30% of SM associated with acute myeloblastic leukaemia (AML); in turn, the KIT mutation is almost systematically restricted to the MC compartment in patients with SM associated with lymphoid neoplasms [26].

    3. Mutations in Genes Other Than KIT

    Emergence of the KIT D816V mutation in an HSC during the development of haematopoietic cells would potentially lead to multilineage involvement of haematopoiesis [65]. This would favour the expansion of neoplastic MCs and an increasing tumour burden; in addition, it might also lead to an increased genomic instability that may facilitate acquisition and accumulation of additional genetic alterations and Table S1) in the KIT-mutated or unmutated HSC and contribute to the malignant transformation of the disease via distinct molecular mechanisms, e.g., activation/repression of anti-/pro-apoptotic mechanisms [67].
    In line with this hypothesis, mutations in genes which are also frequently mutated in other myeloid malignancies are also present at relatively high frequencies in AdvSM patients [68][69][70][71][72][73]. In this regard, it has been recently described that certain DNA methylation patterns may be relevant in the pathogenesis of systemic diseases associated with MC activation [74]. Moreover, a significant number of somatic mutations has been identified in a broad number of genes involved in epigenetic regulatory mechanisms, which have been associated, at least in part, with the pathogenesis, clinical behaviour and evolution of different myeloid neoplasms, including SM [75][76]. Thus, around 30–40% of AdvSM present with an associated myeloid haematological neoplasm already at diagnosis [57], suggesting a close relationship between both malignancies. In line with this, next generation sequencing (NGS) studies have confirmed the presence of recurrent mutations in genes involved in post-transcriptional mRNA processing, epigenetic modification of DNA and transcription and signal transduction factors, in both SM and other myeloid neoplasms [41][68][69][77][78]. Among others, mutations have been recurrently reported in AdvSM in the ASXL1, CBL, DNMT3A, NRAS, RUNX1, SRSF2 and TET2 genes in AdvSM [19][22][36][40][41][68][70][77][78][79][80][81][82][83]. In contrast, the presence of these additional mutations is a relatively infrequent finding in BMM and ISM patients [19][41][68][78][81].

    3.1. Mutations Affecting Transcription Factors and Signalling Pathways

    The correct function and development of the human organism strongly relies on the precise regulation and appropriate production of specific sets of proteins. Gene expression is largely regulated by transcription factors and the activation of processes involved in various intracellular signalling pathways. In this regard, alterations in genes involved in these processes, such as the CBL, JAK2, K/NRAS and/or RUNX1 genes [84], have been associated with several haematological malignancies. To date, mutations in a total of 11 genes related to transcription factors and signalling pathways have been described in patients with different subtypes of SM; of note, while some of these genes have been sporadically reported to be mutated in SM (EPHA7 [70][79], FLT3 [19], IKZF1 [70], PIK3CD [70][79], ROS1 [70][79] and TP53 [19]) (Tables S1 and S2), others (e.g., CBL, JAK2, K/NRAS and RUNX1) are recurrently found to be altered in SM, particularly among SM-AHN patients.
    The CBL (Casitas B-lineage lymphoma proto-oncogene) gene is located on chromosome 11 and encodes for a protein involved in the functional regulation (via competitive blockade) of tyrosine kinase (TK) receptors; in addition, the CBL product also acts in ubiquitination-mediated protein degradation in the proteasome [85][86]. Overall, mutations affecting the CBL gene in myeloid malignancies show a predominance of deletions involving the exon 8 of this gene [87] at frequencies that vary from 15% of patients diagnosed with juvenile myelomonocytic leukaemia, to 13% of CMML (mostly the CBL Y371 mutation) [88][89], 10% of AML and 8% of atypical chronic myeloid leukaemia cases [89][90][91]. Similarly, CBL mutations are found in a variable percentage of SM patients [19][36][68][69][77][80][81], where they are predominantly located at exon 8 (frequently also at codon Y371), their frequency ranging from <1% in Non-AdvSM patients to >10% of AdvSM cases [19][68][71][77][81], including >25% of SM-AHN patients in some cohorts [68][71] (average of 15%). In contrast to other myeloid neoplasms in which the impact of CBL mutations remains unclear [86][89][90][92], their presence in SM has been associated with poorer outcomes [71].
    The JAK2 (Janus Kinase 2) gene is located on human chromosome 9 and encodes a protein that acts as an intracellular (non-receptor) TK that is associated with various cell surface receptors for transducing activating signals through relevant pathways such as the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STATs) pathways [93][94][95]. The most common JAK2 activating mutation, the JAK2 V617F mutation, has been reported in several diagnostic subtypes of MPN [96], which can explain its high incidence (about 11%) in SM-AHN patients [19][40][41][77][97] as compared to other diagnostic subtypes of SM [19][41][68][79][97]. A recent study in SM-AHN patients showed that KIT D816V and JAK2 V617F mutations probably arise in two independent clones in most patients, in which the presence of JAK2 mutations appears to have a low prognostic impact [98].
    The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) and NRAS (Neuroblastoma RAS Viral Oncogene Homolog) genes are both located on chromosome 12, and they encode proteins involved in signalling pathways associated with growth factor membrane receptors through their interaction with membrane GTPases. A large number of somatic mutations involving the KRAS/NRAS genes have been identified, mostly associated with solid tumours such as lung cancer, pancreatic cancer and colorectal cancer, among other prevalent tumours [99][100]; in some of these tumours such as metastatic colorectal cancer, KRAS and NRAS mutations have also been associated with a poorer prognosis [101]. In myeloid neoplasms, NRAS mutations have been associated with the development of AML (7–13%) secondary to different subtypes of MPN; however, it remains unclear whether these mutations directly promote progression to leukaemia [91]. With regards to SM, KRAS and/or NRAS mutations have been sporadically reported in ISM [79][83] and MCL cases [19][68], while they are more frequently found among SM-AHN patients, particularly in cases associated with poor-prognosis myeloid neoplasms (i.e., AML) [19][36][40][41][68][80][102]; in this setting, some researchers have suggested that these mutations might have an adverse prognostic impact [103].
    RUNX1 (Runt-Related Transcription Factor 1) is a gene located on human chromosome 21 that encodes a functional protein that acts as a transcription factor involved in the development of HSC [104]. The most frequent RUNX1 mutations have been associated with progression from MPN to AML [105], which could explain the high frequency of these mutations (up to 37%) among patients with secondary AML [85][91]. In line with these findings, the presence of RUNX1 mutations in patients with MDS is associated with resistance to specific chemotherapeutic drugs and shortened survival [106][107]. In SM, RUNX1 mutations are preferentially located at exons 4 and 5 of the gene [19][22][68][69][70][79][80][83][108], with a frequency that ranges from <1% of Non-AdvSM patients to up to 18% of AdvSM cases, the highest frequency being detected in SM-AHN patients [68][70]. From a prognostic point of view, RUNX1-mutated cases have been associated with an adverse outcome, both among Non-AdvSM and AdvSM patients [69][70][79][83][109].

    3.2. Mutations in Genes Involved in Epigenetic Regulatory Mechanisms

    Although the specific role of each individual epigenetic alteration detected in SM remains unknown [110][111][112][113], recurrent mutations in genes involved in epigenetic modifications of DNA (i.e., ASXL1, CILK1, DNMT3A, EZH2, IDH1, IDH2, KAT6B, NPM1, SETBP1 and TET2 genes) have been recurrently identified; among these, mutations involving the ASXL1, DNMT3A, EZH2 and TET2 genes are the most commonly reported ones.
    The ASXL1 (ASXL transcriptional regulator 1) gene encodes for a protein that interacts with the retinoic acid receptor involved in chromatin remodelling, although its precise function remains largely unknown [114]. The most frequent ASXL1 mutations found in myeloid neoplasms are located at exon 12 [115], with an overall incidence that ranges from <7% of patients with essential thrombocytopenia (ET) or polycythaemia vera (PV), to almost 40% of primary myelofibrosis cases [116]. ASXL1 is also the second most frequently mutated gene in MDS and CMML, and it is altered in up to 30% of AML patients [115][117]. Most reported ASXL1 mutations in SM are also located at exon 12 [19][22][70][77][79][81] with a highly variable frequency that ranges from 1% of BMM cases to >20% of AdvSM patients, particularly of SM-AHN cases. Similarly to other myeloid neoplasms [107][116][118], ASXL1 mutations have been also (recurrently) associated with a worse prognosis in SM [19][69][77][80][81][119].
    The DNMT3A (DNA Methyltransferase 3 Alpha) gene located on chromosome 2, encodes for an enzyme responsible for the methylation of CpG islands, which is critical in various physiological processes during embryogenesis and/or in the inactivation of the X chromosome [120]. The most frequently described mutation in the DNMT3A gene occurs at codon R882 [121], being present in 8–13% of MDS, 26% of AML secondary to MDS and 2% of CMML patients [121][122]. In general, the presence of DNMT3A mutations in patients with myeloid malignancies has been associated with a higher number of blasts in BM and greater leukocyte counts in blood [107][117] in the absence of a clear prognostic impact [117][121][122][123]. Although DNMT3A mutations have been described at relatively similarly low frequencies in Non-AdvSM and AdvSM (4% vs. 6%, respectively), their presence has been associated with a significantly poorer prognosis in some patient cohorts [79][81].
    The EZH2 (Enhancer of Zeste 2 polycomb repressive complex 2 subunit) gene encodes a protein of the PRC2 complex involved in proliferation, differentiation, ageing and maintenance of the chromatin structure through methylation, acting as both a tumour suppressor gene and an oncogene [85]. The EZH2 gene is coded in chromosome 7, and its mutations have been described in both myeloid and lymphoid malignancies, as well as in solid tumours, where they have been recurrently associated with more advanced tumour stages and metastatic disease [124]. In myeloid neoplasms, EZH2 mutations have been described in patients with PV (3%), myelofibrosis (13%), CMML (6%), AML (6%) and MDS (10%) [85][117][123][125][126]; in MDS they have been associated with a worse prognosis [107][126]. In SM, EZH2 mutations have been reported almost exclusively within AdvSM patients [19][22][68][70][119], particularly among ASM and SM-AHN cases.
    The TET2 (Ten–eleven translocation methylcytosine dioxygenase 2) gene is located on chromosome 4 and encodes for a protein that catalyses the conversion of 5-methylcytosine (5-mc) to 5-hydroxymethylcytosine (5-hmc) in the DNA [127]. It is believed that 5-hmc may initiate DNA demethylation by preventing binding to the CpG islands of DNA methyltransferases characteristic of these sequences [128]. To date, TET2 mutations have been described in every exon of the gene, and sometimes mutations involving both alleles coexist in the same cell [70][129]. TET2 mutations are considered to be early events in the development of haematological malignancies such as MPN, MDS, CMML and different subtypes of leukaemia and lymphoma, as well as in SM [129]. Overall, TET2 mutations have been described in about 14% of MPN, 23% of MDS (in which they usually occur together with mutations in SF3B1, U2AF1, ASXL1, SRSF2 and/or DNMT3A and also a normal karyotype [107]) and 30% of CMML patients (often associated with mutations in the SRSF2 and U2AF1 genes) [68][72][107][117][130]. In SM, TET2 is the most frequently mutated gene other than KIT. In these later patients, TET2 mutations have been reported along the entire gene sequence but more frequently at exons 3, 9 and 11. As found also in MDS, the coexistence of TET2 and SRSF2 gene mutations has also been reported in SM [68][119]. Of note, in vitro studies suggest that in a significant proportion of patients with SM-AHN, TET2 mutations may precede the KIT D816V mutation [119], similarly to what would also occur with ASXL1 and SRSF2 mutations. However, despite TET2 mutations being significantly more frequently detected in AdvSM vs. Non-AdvSM patients (39% vs. 3% of the cases, respectively) [22][40][41][68][70][71][77][79][80][81][97][119], and their being associated with the presence of C-findings [41], they do not seem to have any prognostic impact in SM [19][68][69][70][77][79][80][81][83][123].

    3.3. Mutations in Genes Involved in Alternative mRNA Splicing

    The presence of mutations in genes associated with the spliceosome, responsible for alternative RNA processing, has been linked to different diagnostic subtypes of haematopoietic malignancies (e.g., MDS) and some solid tumours (e.g., ocular uveal melanoma or pulmonary fibrosis) [131][132]. These include mutations in the SF3B1, SRSF2 and U2AF1 genes, from which mutations in the former two genes have been described in SM at relatively high frequencies in SM and/or (i.e., SRSF2) in association with poorer outcomes [69][82].
    The SRSF2 (serine and arginine rich splicing factor 2) gene encodes for a protein that is critical for alternative mRNA processing at the post-transcriptional level [133], which also acts as an important regulator of DNA stability, being a key player in the DNA acetylation/phosphorylation network [134]. The most frequent somatic mutations of SRSF2 found in SM patients are located at codon P95 [22][68][70][78][79]. Among patients with other myeloid haematological neoplasms, SRSF2 mutations are particularly frequent (28–30%) among CMML cases [135] and, to a less extent, MDS (11%) and AML (6%) patients [107][117][135]. Recent studies in SM patients show the presence of SRSF2 mutations in a variable percentage of cases ranging from <1% of Non-AdvSM cases to around one third of AdvSM patients, being one of the most frequently mutated genes in SM, particularly in SM-AHN cases [19][22][36][40][68][69][70][78][79][80][81][83]. In contrast to other haematological neoplasms [117][136][137][138], the presence of SRSF2 mutations has been consistently associated with an adverse prognosis in patients with SM [70][83], particularly among AdvSM cases [36][69][80].
    The SF3B1 (splicing factor 3b subunit 1) gene is located in chromosome 2, and it encodes for the largest subunit of the SF3B complex, a core component of the U2 small nuclear ribonucleoprotein of the U2-dependent spliceosome [139]. SF3B1 is the most commonly mutated splicing factor gene in MDS patients [140], in whom it is associated with a more favourable outcome [141]. In contrast to SRSF2, SF3B1 mutations have been less frequently described in SM [19][22][70][79][131][142], with only the K666 codon found to be mutated in more than two patient series. Actually, SF3B1 mutations are detected in <7% of AdvSM patients (most frequently in SM-MDS cases [70][80][119]) (Table S3), while they are rarely found in Non-AdvSM patients [19][68][79][80]. Likewise, U2AF1 mutations are also relatively rare in SM, with a higher incidence in AdvSM [19][40][68] vs. Non-AdvSM cases (6% vs. 1%, respectively) (Table S2); these mutations are mostly located at codons S34 [19][143][144] and Q157 [19] of the U2AF1 gene.

    References

    1. Yarden, Y.; Kuang, W.J.; Yang-Feng, T.; Coussens, L.; Munemitsu, S.; Dull, T.J.; Chen, E.; Schlessinger, J.; Francke, U.; Ullrich, A. Human proto-oncogene c-kit: A new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987, 6, 3341–3351.
    2. Orfao, A.; Garcia-Montero, A.C.; Sanchez, L.; Escribano, L. Recent advances in the understanding of mastocytosis: The role of KIT mutations. Br. J. Haematol. 2007, 138, 12–30.
    3. Li, C.L.; Johnson, G.R. Stem cell factor enhances the survival but not the self-renewal of murine hematopoietic long-term repopulating cells. Blood 1994, 84, 408–414.
    4. Majumder, S.; Brown, K.; Qiu, F.H.; Besmer, P. c-kit protein, a transmembrane kinase: Identification in tissues and characterization. Mol. Cell. Biol. 1988, 8, 4896–4903.
    5. Orfao, A.; Matarraz, S.; Perez-Andres, M.; Almeida, J.; Teodosio, C.; Berkowska, M.A.; van Dongen, J.J.M.; EuroFlow. Immunophenotypic dissection of normal hematopoiesis. J. Immunol. Methods 2019, 475, 112684.
    6. Teodosio, C.; Mayado, A.; Sanchez-Munoz, L.; Morgado, J.M.; Jara-Acevedo, M.; Alvarez-Twose, I.; Garcia-Montero, A.C.; Matito, A.; Caldas, C.; Escribano, L.; et al. The immunophenotype of mast cells and its utility in the diagnostic work-up of systemic mastocytosis. J. Leukoc. Biol. 2015, 97, 49–59.
    7. Okayama, Y.; Kawakami, T. Development, migration, and survival of mast cells. Immunol. Res. 2006, 34, 97–115.
    8. Kitamura, Y.; Hirotab, S. Kit as a human oncogenic tyrosine kinase. Cell. Mol. Life Sci. CMLS 2004, 61, 2924–2931.
    9. Kitayama, H.; Tsujimura, T.; Matsumura, I.; Oritani, K.; Ikeda, H.; Ishikawa, J.; Okabe, M.; Suzuki, M.; Yamamura, K.; Matsuzawa, Y.; et al. Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase. Blood 1996, 88, 995–1004.
    10. Garcia-Montero, A.C.; Jara-Acevedo, M.; Teodosio, C.; Sanchez, M.L.; Nunez, R.; Prados, A.; Aldanondo, I.; Sanchez, L.; Dominguez, M.; Botana, L.M.; et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: A prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 2006, 108, 2366–2372.
    11. Munoz-Gonzalez, J.I.; Garcia-Montero, A.C.; Orfao, A.; Alvarez-Twose, I. Pathogenic and diagnostic relevance of KIT in primary mast cell activation disorders. Ann. Allergy Asthma Immunol. 2021, 127, 427–434.
    12. Valent, P.; Akin, C.; Metcalfe, D.D. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood 2017, 129, 1420–1427.
    13. Akin, C.; Metcalfe, D.D. Systemic Mastocytosis. Annu. Rev. Med. 2004, 55, 419–432.
    14. Jaiswal, S.; Fontanillas, P.; Flannick, J.; Manning, A.; Grauman, P.V.; Mar, B.G.; Lindsley, R.C.; Mermel, C.H.; Burtt, N.; Chavez, A.; et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 2014, 371, 2488–2498.
    15. Escribano, L.; Alvarez-Twose, I.; Sanchez-Munoz, L.; Garcia-Montero, A.; Nunez, R.; Almeida, J.; Jara-Acevedo, M.; Teodosio, C.; Garcia-Cosio, M.; Bellas, C.; et al. Prognosis in adult indolent systemic mastocytosis: A long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J. Allergy Clin. Immunol. 2009, 124, 514–521.
    16. Pullarkat, S.T.; Pullarkat, V.; Kroft, S.H.; Wilson, C.S.; Ahsanuddin, A.N.; Mann, K.P.; Thein, M.; Grody, W.W.; Brynes, R.K. Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia. J. Hematop. 2009, 2, 27–33.
    17. Sotlar, K.; Horny, H.P.; Simonitsch, I.; Krokowski, M.; Aichberger, K.J.; Mayerhofer, M.; Printz, D.; Fritsch, G.; Valent, P. CD25 indicates the neoplastic phenotype of mast cells: A novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am. J. Surg. Pathol. 2004, 28, 1319–1325.
    18. Pignon, J.M.; Giraudier, S.; Duquesnoy, P.; Jouault, H.; Imbert, M.; Vainchenker, W.; Vernant, J.P.; Tulliez, M. A new c-kit mutation in a case of aggressive mast cell disease. Br. J. Haematol. 1997, 96, 374–376.
    19. Pardanani, A.; Lasho, T.; Elala, Y.; Wassie, E.; Finke, C.; Reichard, K.K.; Chen, D.; Hanson, C.A.; Ketterling, R.P.; Tefferi, A. Next-generation sequencing in systemic mastocytosis: Derivation of a mutation-augmented clinical prognostic model for survival. Am. J. Hematol. 2016, 91, 888–893.
    20. Baek, J.O.; Kang, H.K.; Na, S.Y.; Lee, J.R.; Roh, J.Y.; Lee, J.H.; Kim, H.J.; Park, S. N822K c-kit mutation in CD30-positive cutaneous pleomorphic mastocytosis after germ cell tumour of the ovary. Br. J. Dermatol. 2012, 166, 1370–1373.
    21. Arredondo, A.R.; Gotlib, J.; Shier, L.; Medeiros, B.; Wong, K.; Cherry, A.; Corless, C.; Arber, D.A.; Valent, P.; George, T.I. Myelomastocytic leukemia versus mast cell leukemia versus systemic mastocytosis associated with acute myeloid leukemia: A diagnostic challenge. Am. J. Hematol. 2010, 85, 600–606.
    22. Jawhar, M.; Schwaab, J.; Alvarez-Twose, I.; Shoumariyeh, K.; Naumann, N.; Lubke, J.; Perkins, C.; Munoz-Gonzalez, J.I.; Meggendorfer, M.; Kennedy, V.; et al. MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. J. Clin. Oncol. 2019, 37, 2846–2856.
    23. Schwaab, J.; Cabral do, O.H.N.; Naumann, N.; Jawhar, M.; Weiss, C.; Metzgeroth, G.; Schmid, A.; Lubke, J.; Reiter, L.; Fabarius, A.; et al. Importance of Adequate Diagnostic Workup for Correct Diagnosis of Advanced Systemic Mastocytosis. J. Allergy Clin. Immunol. Pract. 2020, 8, 3121–3127.e3121.
    24. Pullarkat, V.A.; Pullarkat, S.T.; Calverley, D.C.; Brynes, R.K. Mast cell disease associated with acute myeloid leukemia: Detection of a new c-kit mutation Asp816His. Am. J. Hematol. 2000, 65, 307–309.
    25. Pullarkat, V.A.; Bueso-Ramos, C.; Lai, R.; Kroft, S.; Wilson, C.S.; Pullarkat, S.T.; Bu, X.; Thein, M.; Lee, M.; Brynes, R.K. Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: Analysis of clinicopathologic features and activating c-kit mutations. Am. J. Hematol. 2003, 73, 12–17.
    26. Sotlar, K.; Colak, S.; Bache, A.; Berezowska, S.; Krokowski, M.; Bultmann, B.; Valent, P.; Horny, H.P. Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD). J. Pathol. 2010, 220, 586–595.
    27. Longley, B.J., Jr.; Metcalfe, D.D.; Tharp, M.; Wang, X.; Tyrrell, L.; Lu, S.Z.; Heitjan, D.; Ma, Y. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc. Natl. Acad. Sci. USA 1999, 96, 1609–1614.
    28. Horny, H.P.; Sotlar, K.; Sperr, W.R.; Valent, P. Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: A histopathological challenge. J. Clin. Pathol. 2004, 57, 604–608.
    29. Nagai, S.; Ichikawa, M.; Takahashi, T.; Sato, H.; Yokota, H.; Oshima, K.; Izutsu, K.; Hangaishi, A.; Kanda, Y.; Motokura, T.; et al. The origin of neoplastic mast cells in systemic mastocytosis with AML1/ETO-positive acute myeloid leukemia. Exp. Hematol. 2007, 35, 1747–1752.
    30. Lasho, T.; Finke, C.; Zblewski, D.; Hanson, C.A.; Ketterling, R.P.; Butterfield, J.H.; Tefferi, A.; Pardanani, A. Concurrent activating KIT mutations in systemic mastocytosis. Br. J. Haematol. 2016, 173, 153–156.
    31. Yabe, M.; Masukawa, A.; Kato, S.; Yabe, H.; Nakamura, N.; Matsushita, H. Systemic mastocytosis associated with t(8;21) acute myeloid leukemia in a child: Detection of the D816A mutation of KIT. Pediatric Blood Cancer 2012, 59, 1313–1316.
    32. Tsutsumi, M.; Miura, H.; Inagaki, H.; Shinkai, Y.; Kato, A.; Kato, T.; Hamada-Tsutsumi, S.; Tanaka, M.; Kudo, K.; Yoshikawa, T.; et al. An aggressive systemic mastocytosis preceded by ovarian dysgerminoma. BMC Cancer 2020, 20, 1162.
    33. Nakamura, R.; Chakrabarti, S.; Akin, C.; Robyn, J.; Bahceci, E.; Greene, A.; Childs, R.; Dunbar, C.E.; Metcalfe, D.D.; Barrett, A.J. A pilot study of nonmyeloablative allogeneic hematopoietic stem cell transplant for advanced systemic mastocytosis. Bone Marrow Transpl. 2006, 37, 353–358.
    34. Heinrich, M.C.; Joensuu, H.; Demetri, G.D.; Corless, C.L.; Apperley, J.; Fletcher, J.A.; Soulieres, D.; Dirnhofer, S.; Harlow, A.; Town, A.; et al. Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin. Cancer Res. 2008, 14, 2717–2725.
    35. Frederiksen, J.K.; Shao, L.; Bixby, D.L.; Ross, C.W. Shared clonal cytogenetic abnormalities in aberrant mast cells and leukemic myeloid blasts detected by single nucleotide polymorphism microarray-based whole-genome scanning. Genes Chromosomes Cancer 2016, 55, 389–396.
    36. Jawhar, M.; Schwaab, J.; Meggendorfer, M.; Naumann, N.; Horny, H.P.; Sotlar, K.; Haferlach, T.; Schmitt, K.; Fabarius, A.; Valent, P.; et al. The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm. Haematologica 2017, 102, 1035–1043.
    37. Lanternier, F.; Cohen-Akenine, A.; Palmerini, F.; Feger, F.; Yang, Y.; Zermati, Y.; Barète, S.; Sans, B.; Baude, C.; Ghez, D.; et al. Phenotypic and Genotypic Characteristics of Mastocytosis According to the Age of Onset. PLoS ONE 2008, 3, e1906.
    38. Valent, P.; Berger, J.; Cerny-Reiterer, S.; Peter, B.; Eisenwort, G.; Hoermann, G.; Mullauer, L.; Mannhalter, C.; Steurer, M.; Bettelheim, P.; et al. Chronic mast cell leukemia (MCL) with KIT S476I: A rare entity defined by leukemic expansion of mature mast cells and absence of organ damage. Ann. Hematol. 2015, 94, 223–231.
    39. Georgin-Lavialle, S.; Lhermitte, L.; Suarez, F.; Yang, Y.; Letard, S.; Hanssens, K.; Feger, F.; Renand, A.; Brouze, C.; Canioni, D.; et al. Mast cell leukemia: Identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor. Eur. J. Haematol. 2012, 89, 47–52.
    40. Rouet, A.; Aouba, A.; Damaj, G.; Soucie, E.; Hanssens, K.; Chandesris, M.O.; Livideanu, C.B.; Dutertre, M.; Durieu, I.; Grandpeix-Guyodo, C.; et al. Mastocytosis among elderly patients: A multicenter retrospective French study on 53 patients. Medicine 2016, 95, e3901.
    41. Soucie, E.; Hanssens, K.; Mercher, T.; Georgin-Lavialle, S.; Damaj, G.; Livideanu, C.; Chandesris, M.O.; Acin, Y.; Létard, S.; de Sepulveda, P.; et al. In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells. Blood 2012, 120, 4846–4849.
    42. Mital, A.; Piskorz, A.; Lewandowski, K.; Wasag, B.; Limon, J.; Hellmann, A. A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib. Eur. J. Haematol. 2011, 86, 531–535.
    43. Zhang, L.Y.; Smith, M.L.; Schultheis, B.; Fitzgibbon, J.; Lister, T.A.; Melo, J.V.; Cross, N.C.; Cavenagh, J.D. A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy. Leuk. Res. 2006, 30, 373–378.
    44. Akin, C.; Fumo, G.; Yavuz, A.S.; Lipsky, P.E.; Neckers, L.; Metcalfe, D.D. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood 2004, 103, 3222–3225.
    45. Broderick, V.; Waghorn, K.; Langabeer, S.E.; Jeffers, M.; Cross, N.C.P.; Hayden, P.J. Molecular response to imatinib in KIT F522C-mutated systemic mastocytosis. Leuk. Res. 2019, 77, 28–29.
    46. Nakagomi, N.; Hirota, S. Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation. Lab. Investig. 2007, 87, 365–371.
    47. Büttner, C.; Henz, B.M.; Welker, P.; Sepp, N.T.; Grabbe, J. Identification of Activating c-kit Mutations in Adult-, but not in Childhood-Onset Indolent Mastocytosis: A Possible Explanation for Divergent Clinical Behavior. J. Investig. Dermatol. 1998, 111, 1227–1231.
    48. Furitsu, T.; Tsujimura, T.; Tono, T.; Ikeda, H.; Kitayama, H.; Koshimizu, U.; Sugahara, H.; Butterfield, J.H.; Ashman, L.K.; Kanayama, Y.; et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J. Clin. Investig. 1993, 92, 1736–1744.
    49. Spector, M.S.; Iossifov, I.; Kritharis, A.; He, C.; Kolitz, J.E.; Lowe, S.W.; Allen, S.L. Mast-cell leukemia exome sequencing reveals a mutation in the IgE mast-cell receptor beta chain and KIT V654A. Leukemia 2012, 26, 1422–1425.
    50. Hartmann, K.; Wardelmann, E.; Ma, Y.; Merkelbach-Bruse, S.; Preussner, L.M.; Woolery, C.; Baldus, S.E.; Heinicke, T.; Thiele, J.; Buettner, R.; et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology 2005, 129, 1042–1046.
    51. Wang, H.J.; Lin, Z.M.; Zhang, J.; Yin, J.H.; Yang, Y. A new germline mutation in KIT associated with diffuse cutaneous mastocytosis in a Chinese family. Clin. Exp. Dermatol. 2014, 39, 146–149.
    52. de Melo Campos, P.; Machado-Neto, J.A.; Scopim-Ribeiro, R.; Visconte, V.; Tabarroki, A.; Duarte, A.S.; Barra, F.F.; Vassalo, J.; Rogers, H.J.; Lorand-Metze, I.; et al. Familial systemic mastocytosis with germline KIT K509I mutation is sensitive to treatment with imatinib, dasatinib and PKC412. Leuk. Res. 2014, 38, 1245–1251.
    53. Alvarez-Twose, I.; Matito, A.; Morgado, J.M.; Sanchez-Munoz, L.; Jara-Acevedo, M.; Garcia-Montero, A.; Mayado, A.; Caldas, C.; Teodosio, C.; Munoz-Gonzalez, J.I.; et al. Imatinib in systemic mastocytosis: A phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget 2017, 8, 68950–68963.
    54. Frost, M.J.; Ferrao, P.T.; Hughes, T.P.; Ashman, L.K. Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol. Cancer Ther. 2002, 1, 1115–1124.
    55. Akin, C.; Brockow, K.; D’Ambrosio, C.; Kirshenbaum, A.S.; Ma, Y.; Longley, B.J.; Metcalfe, D.D. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp. Hematol. 2003, 31, 686–692.
    56. Ma, Y.; Zeng, S.; Metcalfe, D.D.; Akin, C.; Dimitrijevic, S.; Butterfield, J.H.; McMahon, G.; Longley, B.J. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 2002, 99, 1741–1744.
    57. Valent, P.; Horny, H.P.; Escribano, L.; Longley, B.J.; Li, C.Y.; Schwartz, L.B.; Marone, G.; Nunez, R.; Akin, C.; Sotlar, K.; et al. Diagnostic criteria and classification of mastocytosis: A consensus proposal. Leuk. Res. 2001, 25, 603–625.
    58. Yavuz, A.S.; Lipsky, P.E.; Yavuz, S.; Metcalfe, D.D.; Akin, C. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood 2002, 100, 661–665.
    59. Akin, C. Clonality and molecular pathogenesis of mastocytosis. Acta Haematol. 2005, 114, 61–69.
    60. Kocabas, C.N.; Yavuz, A.S.; Lipsky, P.E.; Metcalfe, D.D.; Akin, C. Analysis of the lineage relationship between mast cells and basophils using the c-kit D816V mutation as a biologic signature. J. Allergy Clin. Immunol. 2005, 115, 1155–1161.
    61. Akin, C.; Kirshenbaum, A.S.; Semere, T.; Worobec, A.S.; Scott, L.M.; Metcalfe, D.D. Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis. Exp. Hematol. 2000, 28, 140–147.
    62. Mayado, A.; Teodosio, C.; Dasilva-Freire, N.; Jara-Acevedo, M.; Garcia-Montero, A.C.; Alvarez-Twose, I.; Sanchez-Munoz, L.; Matito, A.; Caldas, C.; Munoz-Gonzalez, J.I.; et al. Characterization of CD34(+) hematopoietic cells in systemic mastocytosis: Potential role in disease dissemination. Allergy 2018, 73, 1294–1304.
    63. Valent, P.; Akin, C.; Arock, M.; Bock, C.; George, T.I.; Galli, S.J.; Gotlib, J.; Haferlach, T.; Hoermann, G.; Hermine, O.; et al. Proposed Terminology and Classification of Pre-Malignant Neoplastic Conditions: A Consensus Proposal. EBioMedicine 2017, 26, 17–24.
    64. Taylor, M.L.; Sehgal, D.; Raffeld, M.; Obiakor, H.; Akin, C.; Mage, R.G.; Metcalfe, D.D. Demonstration that mast cells, T cells, and B cells bearing the activating kit mutation D816V occur in clusters within the marrow of patients with mastocytosis. J. Mol. Diagn. JMD 2004, 6, 335–342.
    65. Garcia-Montero, A.C.; Jara-Acevedo, M.; Alvarez-Twose, I.; Teodosio, C.; Sanchez-Munoz, L.; Muniz, C.; Munoz-Gonzalez, J.I.; Mayado, A.; Matito, A.; Caldas, C.; et al. KIT D816V-mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression. Blood 2016, 127, 761–768.
    66. Jara-Acevedo, M.; Teodosio, C.; Sanchez-Munoz, L.; Alvarez-Twose, I.; Mayado, A.; Caldas, C.; Matito, A.; Morgado, J.M.; Munoz-Gonzalez, J.I.; Escribano, L.; et al. Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: Diagnostic implications. Mod. Pathol. 2015, 28, 1138–1149.
    67. Teodosio, C.; Garcia-Montero, A.C.; Jara-Acevedo, M.; Sanchez-Munoz, L.; Pedreira, C.E.; Alvarez-Twose, I.; Matarraz, S.; Morgado, J.M.; Barcena, P.; Matito, A.; et al. Gene expression profile of highly purified bone marrow mast cells in systemic mastocytosis. J. Allergy Clin. Immunol. 2013, 131, 1213–1224.
    68. Schwaab, J.; Schnittger, S.; Sotlar, K.; Walz, C.; Fabarius, A.; Pfirrmann, M.; Kohlmann, A.; Grossmann, V.; Meggendorfer, M.; Horny, H.P.; et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013, 122, 2460–2466.
    69. Jawhar, M.; Schwaab, J.; Schnittger, S.; Meggendorfer, M.; Pfirrmann, M.; Sotlar, K.; Horny, H.P.; Metzgeroth, G.; Kluger, S.; Naumann, N.; et al. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis. Leukemia 2016, 30, 136–143.
    70. Munoz-Gonzalez, J.I.; Jara-Acevedo, M.; Alvarez-Twose, I.; Merker, J.D.; Teodosio, C.; Hou, Y.; Henriques, A.; Roskin, K.M.; Sanchez-Munoz, L.; Tsai, A.G.; et al. Impact of somatic and germline mutations on the outcome of systemic mastocytosis. Blood Adv. 2018, 2, 2814–2828.
    71. Pardanani, A.D.; Lasho, T.L.; Finke, C.; Zblewski, D.L.; Abdelrahman, R.A.; Wassie, E.A.; Gangat, N.; Hanson, C.A.; Ketterling, R.P.; Tefferi, A. ASXL1 and CBL mutations are independently predictive of inferior survival in advanced systemic mastocytosis. Br. J. Haematol. 2016, 175, 534–536.
    72. Papaemmanuil, E.; Gerstung, M.; Malcovati, L.; Tauro, S.; Gundem, G.; Van Loo, P.; Yoon, C.J.; Ellis, P.; Wedge, D.C.; Pellagatti, A.; et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013, 122, 3616–3699.
    73. Bejar, R. CHIP, ICUS, CCUS and other four-letter words. Leukemia 2017, 31, 1869–1871.
    74. Haenisch, B.; Frohlich, H.; Herms, S.; Molderings, G.J. Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease. Immunogenetics 2014, 66, 287–297.
    75. Itzykson, R.; Fenaux, P. Epigenetics of myelodysplastic syndromes. Leukemia 2014, 28, 497–506.
    76. Shih, A.H.; Abdel-Wahab, O.; Patel, J.P.; Levine, R.L. The role of mutations in epigenetic regulators in myeloid malignancies. Nature reviews. Cancer 2012, 12, 599–612.
    77. Damaj, G.; Joris, M.; Chandesris, O.; Hanssens, K.; Soucie, E.; Canioni, D.; Kolb, B.; Durieu, I.; Gyan, E.; Livideanu, C.; et al. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS ONE 2014, 9, 85362.
    78. Hanssens, K.; Brenet, F.; Agopian, J.; Georgin-Lavialle, S.; Damaj, G.; Cabaret, L.; Chandesris, M.O.; de Sepulveda, P.; Hermine, O.; Dubreuil, P.; et al. SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes. Haematologica 2014, 99, 830–835.
    79. Munoz-Gonzalez, J.I.; Alvarez-Twose, I.; Jara-Acevedo, M.; Henriques, A.; Vinas, E.; Prieto, C.; Sanchez-Munoz, L.; Caldas, C.; Mayado, A.; Matito, A.; et al. Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis. Blood 2019, 134, 456–468.
    80. Naumann, N.; Jawhar, M.; Schwaab, J.; Kluger, S.; Lubke, J.; Metzgeroth, G.; Popp, H.D.; Khaled, N.; Horny, H.P.; Sotlar, K.; et al. Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis. Genes Chromosomes Cancer 2018, 57, 252–259.
    81. Traina, F.; Visconte, V.; Jankowska, A.M.; Makishima, H.; O’Keefe, C.L.; Elson, P.; Han, Y.; Hsieh, F.H.; Sekeres, M.A.; Mali, R.S.; et al. Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis. PLoS ONE 2012, 7, e43090.
    82. Jawhar, M.; Schwaab, J.; Hausmann, D.; Clemens, J.; Naumann, N.; Henzler, T.; Horny, H.P.; Sotlar, K.; Schoenberg, S.O.; Cross, N.C.; et al. Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis. Leukemia 2016, 30, 2342–2350.
    83. Munoz-Gonzalez, J.I.; Alvarez-Twose, I.; Jara-Acevedo, M.; Zanotti, R.; Perkins, C.; Jawhar, M.; Sperr, W.R.; Shoumariyeh, K.; Schwaab, J.; Greiner, G.; et al. Proposed global prognostic score for systemic mastocytosis: A retrospective prognostic modelling study. Lancet Haematol 2021, 8, e194–e204.
    84. Latchman, D.S. Transcription-Factor Mutations and Disease. N. Engl. J. Med. 1996, 334, 28–33.
    85. Vainchenker, W.; Delhommeau, F.; Constantinescu, S.N.; Bernard, O.A. New mutations and pathogenesis of myeloproliferative neoplasms. Blood 2011, 118, 1723–1735.
    86. Kales, S.C.; Ryan, P.E.; Nau, M.M.; Lipkowitz, S. Cbl and human myeloid neoplasms: The Cbl oncogene comes of age. Cancer Res. 2010, 70, 4789–4794.
    87. Sargin, B.; Choudhary, C.; Crosetto, N.; Schmidt, M.H.; Grundler, R.; Rensinghoff, M.; Thiessen, C.; Tickenbrock, L.; Schwable, J.; Brandts, C.; et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 2007, 110, 1004–1012.
    88. Caligiuri, M.A.; Briesewitz, R.; Yu, J.; Wang, L.; Wei, M.; Arnoczky, K.J.; Marburger, T.B.; Wen, J.; Perrotti, D.; Bloomfield, C.D.; et al. Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood 2007, 110, 1022–1024.
    89. Reindl, C.; Quentmeier, H.; Petropoulos, K.; Greif, P.A.; Benthaus, T.; Argiropoulos, B.; Mellert, G.; Vempati, S.; Duyster, J.; Buske, C.; et al. CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin. Cancer Res. 2009, 15, 2238–2247.
    90. Grand, F.H.; Hidalgo-Curtis, C.E.; Ernst, T.; Zoi, K.; Zoi, C.; McGuire, C.; Kreil, S.; Jones, A.; Score, J.; Metzgeroth, G.; et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 2009, 113, 6182–6192.
    91. Beer, P.A.; Delhommeau, F.; LeCouedic, J.P.; Dawson, M.A.; Chen, E.; Bareford, D.; Kusec, R.; McMullin, M.F.; Harrison, C.N.; Vannucchi, A.M.; et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood 2010, 115, 2891–2900.
    92. Makishima, H.; Cazzolli, H.; Szpurka, H.; Dunbar, A.; Tiu, R.; Huh, J.; Muramatsu, H.; O’Keefe, C.; Hsi, E.; Paquette, R.L.; et al. Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J. Clin. Oncol. 2009, 27, 6109–6116.
    93. Villarino, A.V.; Kanno, Y.; O’Shea, J.J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 2017, 18, 374–384.
    94. Bader, M.S.; Meyer, S.C. JAK2 in Myeloproliferative Neoplasms: Still a Protagonist. Pharmaceuticals 2022, 15, 160.
    95. Guo, Y.J.; Pan, W.W.; Liu, S.B.; Shen, Z.F.; Xu, Y.; Hu, L.L. ERK/MAPK signalling pathway and tumorigenesis. Exp. Ther. Med. 2020, 19, 1997–2007.
    96. Szybinski, J.; Meyer, S.C. Genetics of Myeloproliferative Neoplasms. Hematol. Oncol. Clin. N Am. 2021, 35, 217–236.
    97. Tefferi, A.; Levine, R.L.; Lim, K.H.; Abdel-Wahab, O.; Lasho, T.L.; Patel, J.; Finke, C.M.; Mullally, A.; Li, C.Y.; Pardanani, A.; et al. Frequent TET2 mutations in systemic mastocytosis: Clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 2009, 23, 900–904.
    98. Naumann, N.; Lubke, J.; Shomali, W.; Reiter, L.; Horny, H.P.; Jawhar, M.; Dangelo, V.; Fabarius, A.; Metzgeroth, G.; Kreil, S.; et al. Clinical and histopathological features of myeloid neoplasms with concurrent Janus kinase 2 (JAK2) V617F and KIT proto-oncogene, receptor tyrosine kinase (KIT) D816V mutations. Br. J. Haematol. 2021, 194, 344–354.
    99. Chiosea, S.I.; Sherer, C.K.; Jelic, T.; Dacic, S. KRAS mutant allele-specific imbalance in lung adenocarcinoma. Mod. Pathol. 2011, 24, 1571–1577.
    100. Krasinskas, A.M.; Moser, A.J.; Saka, B.; Adsay, N.V.; Chiosea, S.I. KRAS mutant allele-specific imbalance is associated with worse prognosis in pancreatic cancer and progression to undifferentiated carcinoma of the pancreas. Mod. Pathol. 2013, 26, 1346–1354.
    101. Chang, Y.Y.; Lin, J.K.; Lin, T.C.; Chen, W.S.; Jeng, K.J.; Yang, S.H.; Wang, H.S.; Lan, Y.T.; Lin, C.C.; Liang, W.Y.; et al. Impact of KRAS mutation on outcome of patients with metastatic colorectal cancer. Hepato Gastroenterol. 2014, 61, 1946–1953.
    102. Wilson, T.M.; Maric, I.; Simakova, O.; Bai, Y.; Chan, E.C.; Olivares, N.; Carter, M.; Maric, D.; Robyn, J.; Metcalfe, D.D. Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis. Haematologica 2011, 96, 459–463.
    103. Pardanani, A.; Shah, S.; Mannelli, F.; Elala, Y.C.; Guglielmelli, P.; Lasho, T.L.; Patnaik, M.M.; Gangat, N.; Ketterling, R.P.; Reichard, K.K.; et al. Mayo alliance prognostic system for mastocytosis: Clinical and hybrid clinical-molecular models. Blood Adv. 2018, 2, 2964–2972.
    104. Ichikawa, M.; Goyama, S.; Asai, T.; Kawazu, M.; Nakagawa, M.; Takeshita, M.; Chiba, S.; Ogawa, S.; Kurokawa, M. AML1/Runx1 Negatively Regulates Quiescent Hematopoietic Stem Cells in Adult Hematopoiesis. J. Immunol. 2008, 180, 4402–4408.
    105. Ding, Y.; Harada, Y.; Imagawa, J.; Kimura, A.; Harada, H. AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms. Blood 2009, 114, 5201–5205.
    106. Gaidzik, V.I.; Bullinger, L.; Schlenk, R.F.; Zimmermann, A.S.; Rock, J.; Paschka, P.; Corbacioglu, A.; Krauter, J.; Schlegelberger, B.; Ganser, A.; et al. RUNX1 mutations in acute myeloid leukemia: Results from a comprehensive genetic and clinical analysis from the AML study group. J. Clin. Oncol. 2011, 29, 1364–1372.
    107. Bejar, R.; Stevenson, K.E.; Caughey, B.A.; Abdel-Wahab, O.; Steensma, D.P.; Galili, N.; Raza, A.; Kantarjian, H.; Levine, R.L.; Neuberg, D.; et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J. Clin. Oncol. 2012, 30, 3376–3382.
    108. Jawhar, M.; Schwaab, J.; Naumann, N.; Horny, H.-P.; Sotlar, K.; Haferlach, T.; Metzgeroth, G.; Fabarius, A.; Valent, P.; Hofmann, W.-K.; et al. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood 2017, 130, 137–145.
    109. Pardanani, A.; Lasho, T.; Barraco, D.; Patnaik, M.; Elala, Y.; Tefferi, A. Next generation sequencing of myeloid neoplasms with eosinophilia harboring the FIP1L1-PDGFRA mutation. Am. J. Hematol. 2016, 91, 10–11.
    110. Sharma, S.; Kelly, T.K.; Jones, P.A. Epigenetics in cancer. Carcinogenesis 2010, 31, 27–36.
    111. Figueroa, M.E.; Lugthart, S.; Li, Y.; Erpelinck-Verschueren, C.; Deng, X.; Christos, P.J.; Schifano, E.; Booth, J.; van Putten, W.; Skrabanek, L.; et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010, 17, 13–27.
    112. Reszka, E.; Jablonska, E.; Wieczorek, E.; Valent, P.; Arock, M.; Nilsson, G.; Nedoszytko, B.; Niedoszytko, M. Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis. Int. J. Mol. Sci. 2021, 22, 2964.
    113. Gorska, A.; Jablonska, E.; Reszka, E.; Niedoszytko, M.; Lange, M.; Gruchala-Niedoszytko, M.; Jarczak, J.; Strapagiel, D.; Gorska-Ponikowska, M.; Bastian, P.; et al. DNA methylation profile in patients with indolent systemic mastocytosis. Clin. Transl. Allergy 2021, 11, e12074.
    114. Katoh, M. Functional and cancer genomics of ASXL family members. Br. J. Cancer 2013, 109, 299–306.
    115. Gelsi-Boyer, V.; Trouplin, V.; Adelaide, J.; Bonansea, J.; Cervera, N.; Carbuccia, N.; Lagarde, A.; Prebet, T.; Nezri, M.; Sainty, D.; et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br. J. Haematol. 2009, 145, 788–800.
    116. Carbuccia, N.; Murati, A.; Trouplin, V.; Brecqueville, M.; Adelaide, J.; Rey, J.; Vainchenker, W.; Bernard, O.A.; Chaffanet, M.; Vey, N.; et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 2009, 23, 2183–2186.
    117. Kar, S.A.; Jankowska, A.; Makishima, H.; Visconte, V.; Jerez, A.; Sugimoto, Y.; Muramatsu, H.; Traina, F.; Afable, M.; Guinta, K.; et al. Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. Haematologica 2013, 98, 107–113.
    118. Tefferi, A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010, 24, 1128–1138.
    119. Jawhar, M.; Schwaab, J.; Schnittger, S.; Sotlar, K.; Horny, H.P.; Metzgeroth, G.; Muller, N.; Schneider, S.; Naumann, N.; Walz, C.; et al. Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event. Leukemia 2015, 29, 1115–1122.
    120. Jia, Y.; Li, P.; Fang, L.; Zhu, H.; Xu, L.; Cheng, H.; Zhang, J.; Li, F.; Feng, Y.; Li, Y.; et al. Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer. Cell Discov. 2016, 2, 16007.
    121. Walter, M.J.; Ding, L.; Shen, D.; Shao, J.; Grillot, M.; McLellan, M.; Fulton, R.; Schmidt, H.; Kalicki-Veizer, J.; O’Laughlin, M.; et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 2011, 25, 1153–1158.
    122. Tie, R.; Zhang, T.; Fu, H.; Wang, L.; Wang, Y.; He, Y.; Wang, B.; Zhu, N.; Fu, S.; Lai, X.; et al. Association between DNMT3A mutations and prognosis of adults with de novo acute myeloid leukemia: A systematic review and meta-analysis. PLoS ONE 2014, 9, e93353.
    123. Jankowska, A.M.; Makishima, H.; Tiu, R.V.; Szpurka, H.; Huang, Y.; Traina, F.; Visconte, V.; Sugimoto, Y.; Prince, C.; O’Keefe, C.; et al. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 2011, 118, 3932–3941.
    124. Chase, A.; Cross, N.C.P. Aberrations of EZH2 in Cancer. Clinical Cancer Res. 2011, 17, 2613–2618.
    125. Ernst, T.; Chase, A.J.; Score, J.; Hidalgo-Curtis, C.E.; Bryant, C.; Jones, A.V.; Waghorn, K.; Zoi, K.; Ross, F.M.; Reiter, A.; et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet 2010, 42, 722–726.
    126. Nikoloski, G.; Langemeijer, S.M.C.; Kuiper, R.P.; Knops, R.; Massop, M.; Tonnissen, E.R.L.T.M.; van der Heijden, A.; Scheele, T.N.; Vandenberghe, P.; de Witte, T.; et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat. Genet 2010, 42, 665–667.
    127. Ito, S.; D’Alessio, A.C.; Taranova, O.V.; Hong, K.; Sowers, L.C.; Zhang, Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010, 466, 1129–1133.
    128. Tan, L.; Shi, Y.G. Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 2012, 139, 1895–1902.
    129. Holmfeldt, L.; Mullighan, C.G. The role of TET2 in hematologic neoplasms. Cancer Cell 2011, 20, 1–2.
    130. Delhommeau, F.; Dupont, S.; Della Valle, V.; James, C.; Trannoy, S.; Masse, A.; Kosmider, O.; Le Couedic, J.P.; Robert, F.; Alberdi, A.; et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 2009, 360, 2289–2301.
    131. Visconte, V.; Makishima, H.; Maciejewski, J.P.; Tiu, R.V. Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders. Leukemia 2012, 26, 2447–2454.
    132. Bejar, R. Splicing Factor Mutations in Cancer. Adv. Exp. Med. Biol. 2016, 907, 215–228.
    133. Fu, X.D. Specific commitment of different pre-mRNAs to splicing by single SR proteins. Nature 1993, 365, 82–85.
    134. Edmond, V.; Moysan, E.; Khochbin, S.; Matthias, P.; Brambilla, C.; Brambilla, E.; Gazzeri, S.; Eymin, B. Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin. EMBO J. 2011, 30, 510–523.
    135. Yoshida, K.; Sanada, M.; Shiraishi, Y.; Nowak, D.; Nagata, Y.; Yamamoto, R.; Sato, Y.; Sato-Otsubo, A.; Kon, A.; Nagasaki, M.; et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011, 478, 64–69.
    136. Meggendorfer, M.; Roller, A.; Haferlach, T.; Eder, C.; Dicker, F.; Grossmann, V.; Kohlmann, A.; Alpermann, T.; Yoshida, K.; Ogawa, S.; et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood 2012, 120, 3080–3088.
    137. Thol, F.; Kade, S.; Schlarmann, C.; Loffeld, P.; Morgan, M.; Krauter, J.; Wlodarski, M.W.; Kolking, B.; Wichmann, M.; Gorlich, K.; et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 2012, 119, 3578–3584.
    138. Mian, S.A.; Smith, A.E.; Kulasekararaj, A.G.; Kizilors, A.; Mohamedali, A.M.; Lea, N.C.; Mitsopoulos, K.; Ford, K.; Nasser, E.; Seidl, T.; et al. Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome. Haematologica 2013, 98, 1058–1066.
    139. Will, C.L.; Luhrmann, R. Spliceosome structure and function. Cold Spring Harb. Perspect. Biol. 2011, 3, a003707.
    140. Pellagatti, A.; Armstrong, R.N.; Steeples, V.; Sharma, E.; Repapi, E.; Singh, S.; Sanchi, A.; Radujkovic, A.; Horn, P.; Dolatshad, H.; et al. Impact of spliceosome mutations on RNA splicing in myelodysplasia: Dysregulated genes/pathways and clinical associations. Blood 2018, 132, 1225–1240.
    141. Malcovati, L.; Papaemmanuil, E.; Bowen, D.T.; Boultwood, J.; Della Porta, M.G.; Pascutto, C.; Travaglino, E.; Groves, M.J.; Godfrey, A.L.; Ambaglio, I.; et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 2011, 118, 6239–6246.
    142. Cross, N.C.P.; Hoade, Y.; Tapper, W.J.; Carreno-Tarragona, G.; Fanelli, T.; Jawhar, M.; Naumann, N.; Pieniak, I.; Lubke, J.; Ali, S.; et al. Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia 2019, 33, 415–425.
    143. Graubert, T.A.; Shen, D.; Ding, L.; Okeyo-Owuor, T.; Lunn, C.L.; Shao, J.; Krysiak, K.; Harris, C.C.; Koboldt, D.C.; Larson, D.E.; et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet 2011, 44, 53–57.
    144. Hirabayashi, S.; Flotho, C.; Moetter, J.; Heuser, M.; Hasle, H.; Gruhn, B.; Klingebiel, T.; Thol, F.; Schlegelberger, B.; Baumann, I.; et al. Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML. Blood 2012, 119, e96–e99.
    More
    Information
    Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , ,
    View Times: 132
    Revisions: 2 times (View History)
    Update Date: 27 May 2022
    Table of Contents
      1000/1000

      Confirm

      Are you sure you want to delete?

      Video Upload Options

      Do you have a full video?
      Cite
      If you have any further questions, please contact Encyclopedia Editorial Office.
      González-López, Ó.; Garcia-Montero, A.C.; Orfao, A. Gene Mutations in Systemic Mastocytosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/23424 (accessed on 07 February 2023).
      González-López Ó, Garcia-Montero AC, Orfao A. Gene Mutations in Systemic Mastocytosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/23424. Accessed February 07, 2023.
      González-López, Óscar, Andres C. Garcia-Montero, Alberto Orfao. "Gene Mutations in Systemic Mastocytosis," Encyclopedia, https://encyclopedia.pub/entry/23424 (accessed February 07, 2023).
      González-López, Ó., Garcia-Montero, A.C., & Orfao, A. (2022, May 26). Gene Mutations in Systemic Mastocytosis. In Encyclopedia. https://encyclopedia.pub/entry/23424
      González-López, Óscar, et al. ''Gene Mutations in Systemic Mastocytosis.'' Encyclopedia. Web. 26 May, 2022.
      Top
      Feedback