Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 2166 word(s) 2166 2021-12-13 07:52:58 |
2 format correct Meta information modification 2166 2021-12-21 08:41:38 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Houshmand, M. Targeting CML LSCs. Encyclopedia. Available online: https://encyclopedia.pub/entry/17324 (accessed on 18 April 2024).
Houshmand M. Targeting CML LSCs. Encyclopedia. Available at: https://encyclopedia.pub/entry/17324. Accessed April 18, 2024.
Houshmand, Mohammad. "Targeting CML LSCs" Encyclopedia, https://encyclopedia.pub/entry/17324 (accessed April 18, 2024).
Houshmand, M. (2021, December 20). Targeting CML LSCs. In Encyclopedia. https://encyclopedia.pub/entry/17324
Houshmand, Mohammad. "Targeting CML LSCs." Encyclopedia. Web. 20 December, 2021.
Targeting CML LSCs
Edit

Chronic myeloid leukemia stem cells (CML LSCs) are a rare and quiescent population that are resistant to tyrosine kinase inhibitors (TKI). When TKI therapy is discontinued in CML patients in deep, sustained and apparently stable molecular remission, these cells in approximately half of the cases restart to grow, resuming the leukemic process. The elimination of these TKI resistant leukemic stem cells is therefore an essential step in increasing the percentage of those patients who can reach a successful long-term treatment free remission (TFR). The understanding of the biology of the LSCs and the identification of the differences, phenotypic and/or metabolic, that could eventually allow them to be distinguished from the normal hematopoietic stem cells (HSCs) are therefore important steps in designing strategies to target LSCs in a rather selective way, sparing the normal counterparts.

chronic myeloid leukemia leukemia stem cells

1. WNT Signaling Pathway

The WNT signaling pathway has been shown to have a significant role in the development of several organs including the hematopoietic system while perturbation of this crucial pathway sparks induction of various types of cancers. In the resting condition, the WNT-β catenin network forms a destruction complex including AXIN, adenomatous polyposis coli (APC), Casein kinase 1 (CK1) and Glycogen synthase kinase 3 (GSK3) and links to β-catenin, providing a binding site for the ubiquitin ligase that leads to β catenin degradation in the proteasome. By contrast, following attachment of WNT to the frizzled receptor (FR), GSK3, CK1, and AXIN bind Lipoprotein receptor-related proteins (LRP) and leave β-catenin free for nucleus localization where it interacts with transcription factors of the TCF/LEF family and promotes gene expression. It has been demonstrated that β-catenin is of paramount importance for self-renewal and long-term maintenance of both HSCs and LSCs [1]. After induction of BCR-ABL in β-catenin null mice, defect in self-renewal and in engraftment potential of CML LSCs has been observed and this shows that this pathway is essential for normal and leukemic stem cells survival [2]. It has been shown that BCR-ABL has direct contact with β-catenin and mediates the nucleus transition by making this protein more stable. Furthermore, expression of β-catenin increases with CML progression and is responsible for the increased self-renewal of CML progenitors in blast crisis [3]. In the bone marrow niche, mesenchymal cells may interact with CML LSCs through the WNT/β- catenin pathway enhancing their proliferation. Therefore, increased expression of β-catenin can be seen as a form of resistance of LSCs allowing their survival [4][5] and a combination of WNT/β-catenin inhibitors and TKI could potentially help to get rid of CML LSCs. However, unfortunately this approach has been demonstrated to be too toxic also for normal HSCs as well as for the stem cells of other organs and, at least for the moment, has been abandoned [6][7].

2. Hedgehog Signaling Pathway

The Hedgehog signaling pathway which is essential for hematopoiesis, is deregulated in several solid tumors. It is initiated through binding of hedgehog (Hh) ligands (Sonic Hh, Indian Hh, and Desert Hh) to a seven transmembrane receptor called Patched (Ptch). After the consequent activation of the Smoothened protein (Smo) by Ptch, Glioma-Associated Oncogene Homolog (Gli) family transcription factors are activated, which are able to transcribe target genes such as Gli1, Ptch1, bcl2, Cyclin D, and MYC [8]. In CML high mRNA expression of Hedgehog cascade related proteins underlines the role of this pathway in driving leukemogenesis [9]. ABL kinase is not needed for the salvation of this cascade [10]. Whereas studies suggest that Smo targeting does not affect the engraftment potential and the fate decision of normal HSCs, it has been shown that it may potentially reduce the engraftment ability and the colony formation of CML LSCs. Therefore, hitting this pathway should selectively affect LSCs but not normal HSCs [10][11]. Indeed, exposure of CML cells containing both wild type BCR-ABL and BCR-ABL1 mutated T315I cells to an Smo inhibitor led to the purging of the mutated clone [12]. Another study demonstrated that the use of Hedgehog inhibitors not only propels CML LSCs into cycling condition but also restores their susceptibility to TKI [11][13]. Again, however clinical trials testing the usefulness of this approach have shown that Hh pathway inhibitors are too toxic and have been finally abandoned.

3. PI3K-AKT Pathway

The known participation of the Phosphatidylinositol-3-kinase (PI3K) signaling pathway in the maintenance and function of normal HSCs drove the attention on the possible role of this cascade in the LSC population. By phosphorylation of phosphatidylinositol (3,4)-bisphosphate (PIP2) by PI3K and formation of phosphatidylinositol-3,4,5-trisphosphate (PIP3), Pyruvate Dehydrogenase Kinase 1 (PDK1) is recruited and associated to PIP3 and phosphorylates AKT, that subsequently activates mTORC1 and phosphorylates the Forkhead box O (FOXO) transcription factors family [14]. It has been shown that this signaling pathway is activated by BCR-ABL1 and so, in the Ph-positive cell population, it may be more specific with respect to the WNT and Hedgehog signaling pathways. When the BCR-ABL TK activity is on, AKT phosphorylates FOXO transcription factors and does not allow their shift to the nucleus, but TKIs blocking BCR-ABL1 TK activity can promote FOXO nucleus relocalization, restoring their transcriptional activity. Expression of BCL6, that is considered essential for the survival of CML stem cells, and also ATM and CDKN1C, is enhanced by the FOXO transcriptional activity [14][15]. Inhibition of mTORC1 did not show an evident effect on CML LSCs, but inhibition of PI3K can restore the vulnerability of CML LSCs to TKIs [16].

4. JAK-STAT Pathway

In addition, the JAK-STAT pathway plays an important role in CML, but in a strong association with BCR-ABL1 kinase activity. Indeed, STAT1, STAT3, and STAT5 can be activated by BCR-ABL1 directly or indirectly through JAK2 induction and activation by BCR-ABL1. JAK2 activation can be also stimulated by growth factors produced by the mesenchymal cells of the hematopoietic bone marrow niche [17][18]. It has been shown that inhibition of the JAK2 by ruxolitinib may reduce the level of BCR-ABL1 protein and may help to overcome resistance [19]. It was also seen that the combination of Imatinib + INFγ is able to decrease the phosphorylation of STAT5, but it increases the phosphorylation of STAT1, an up-regulator of the survival hint induced by BCL6, clearly delineating another potential pitfall of imatinib and of TKI therapy in general [20]. In line with these concepts, the use of ruxolitinib (a JAKs inhibitor) together with nilotinib fruitfully in vitro showed activity in suppressing the CML LSC population, without affecting the HSCs. However clinical trials testing this strategy were unsuccessful. It has also been reported that STAT3 dysregulates CML LSC metabolism, and its inhibition may eradicate these resistant cells [21]. Meanwhile, glitazones an antidiabetic drug by activating peroxisome proliferator-activated receptor-γ (PPARγ) reduces expression of STAT5 that might lead to the elimination of the CML LSC population [22].
Possible signaling pathways are shown in Figure 1.
Figure 1. Possible signaling pathways in CML LSCs.

5. Other Players

5.1. Blk

It has been shown that Blk as a tyrosine kinase protein has a diminished expression in CML LSCs in contrast to normal cells. Although Blk is regarded as a tumor suppressor, in CML LSCs, via upregulation of p27, BCR-ABL1 downsizes the expression of this protein by modulation of c-myc and Pax5. Meanwhile, overexpression of Blk in CML LSCs inhibits the self-renewal and increases the apoptosis rate, while Blk knock-down does not interfere with the regular HSC activity [23].

5.2. EZH2

EZH2 as part of the PRC2 complex mediates repression of various genes by trimethylation of histone H3 (H3K27me3). Amplification of EZH2 in CML LSCs and reduction after TKI therapy shows its engagement in the pathogenesis of CML and its dependency on BCR-ABL1 TK activity. It has also been reported that EZH2 inhibitor increases the possibility of CML LSC eradication while sparing the normal HSCs. This effect is enhanced by the combination of TKI and EZH2 Inhibitor [24].

5.3. Fap-1

Another pathway associated with resistance to elimination is the enhanced expression of Fap-1 in CML LSCs. Fap-1 with its phosphatase activity blocks Fas mediated apoptosis and also stabilizes β-catenin by targeting its inhibitor Gsk3β. Fap-1 activity is accompanied by persistence of CML stem cells and Fap-1 inhibition promotes TKI response and hampers the progression of leukemic cells [25].

5.4. HIF-1

Hypoxia inducible factor (HIF), constituted of α and β subunits, increases when oxygen concentration is low in order to facilitate the cell adaptation to this new environment. HIF-1 as a transcription factor has a crucial role in regulating survival, proliferation, and maintenance of CML LSCs. Cheloni et al., posited that using acriflavine, an HIF-1 inhibitor, significantly affects the fate of CML cells by c-MYC down regulation and decrease of stemness genes like NANOG, SOX2, and OCT4. As CML LSCs are more dependent on HIF-1 than normal HSCs, the combination of an HIF-1 inhibitor with TKI could represent a new form of strategy to target resistant CML LSCs that reside in the hypoxic region [26][27].

5.5. PML

The promyelocyte leukemia protein (PML), by attending in the formation of PML-nuclear bodies (PML-NBs), acts as a tumor suppressor and transcription factor and plays a pivotal role in apoptosis and senescence of normal cells [28]. The PML gene is already well known because of its involvement in the t(15;17) translocation that causes the fusion of PML with retinoic acid receptor alpha (RAR-alpha) in acute promyelocyte leukemia (APL), determining a differentiation arrest [29]. Besides, up-regulation of PML in CML LSCs may hamper the cycling of these cells and cause a decrease in their sensitivity to TKIs. It has been shown that targeting PML in CML cells by arsenic trioxide (As2O3) leads to PML degradation and triggers cycling of these quiescent cells. This strategy may promote the exhaustion of the CML LSCs restoring their sensitivity to the TKIs [30].

5.6. PP2A

Protein phosphatase 2 A (PP2A), a serine/threonine phosphatase which is composed by the scaffold (A), regulatory (B), and catalytic (C) subunits, has a role in directing β-catenin pathway, programmed cell death and cell cycle progression [31]. Until now our knowledge about the role of PP2A in CML LSCs has been limited to its tumor inhibitory effect. In CML this protein is regulated by SET protein activity, and enhancement of SET during the progression of CML from chronic to more advanced phases of the disease determines the downregulation of PP2A. It has been shown that in the LSC population, PP2A reduction provides a stimulus for self-renewal of leukemic cells. Restoring its activity could therefore be useful to decrease the LSC pool [32]. Various isoforms of PP2A, however are present and while some of them play a suppressive role in many cancers, other isoforms can act differently [31]. Recently, however, Lai et al. demonstrated that inhibition of PP2A and TKI may efficiently suppress CML LSCs [33].

5.7. ALOX5

ALOX5 encodes 5-lypoxygenase (5-LO) that converts arachidonic acid into leukotrienes and is involved in inflammatory condition and cancer development [34]. Targeting ALOX5 hampers the differentiation, the function, and the survival of CML LSCs, while normal HSCs remain uninfluenced. Zileuton (5-LO inhibitor) impairs CML LSC development [35], but although the oncogenicity of ALOX5 in the mouse model seemed to be compelling, in CML patients it has a low expression and the use of a 5-LO inhibitor does not show particular consequences [36].

5.8. SIRT1

Sirtuin 1 (SIRT1) is a histone deacetylase that regulates gene expression, metabolic activity and aging within cells [37]. SIRT1 overexpression in primary CML cells deacetylates many transcription factors including P53, Ku70, and FOX01. This genetic modification promotes drug resistance, survival, and propagation of the leukemic fraction [38][39]. SIRT1 targeting in CML LSCs, both by inhibition or knock-down, enhances acetylation of P53 which gives rise to apoptosis and reduction of their growth [40]. So, applying the combination of TKI and SIRT1 inhibitor maybe a potential approach to tackle leukemogenesis.
Considering the role of different molecules in supporting CML LSC survival and proliferation, many clinical trials have been designed to target these players and are summarized in Table 1.
Table 1. Clinical trials that used non-TKI agents for the treatment of CML.
CML Clinical Trial with New Therapeutic Agents (Non-TKIs)
Generic Name Brand Name Clinical Trial Identifier Target Start Date Status
Sirolimus Rapamune NCT00101088 mTOR inhibitors 10-Jan-05 Terminated
Sorafenib Nexavar NCT00661180 Multikinase inhibitors, VEGF/VEGFR inhibitors 18-Apr-08 Completed
Sunitinib Sutent NCT00387426 Multikinase inhibitors, VEGF/VEGFR inhibitors 13-Oct-06 Completed
Ruxolitinib Jakafi NCT02253277 JAK/STAT inhibitors 1-Oct-14 Completed
Axitinib Inlyta NCT02782403 Multikinase inhibitors, VEGF/VEGFR inhibitors 25-May-16 Terminated
Ibrutinib Imbruvica NCT03267186 BTK inhibitors 30-Aug-17 Ongoing
Midostaurin Rydapt NCT02115295 Multikinase inhibitors 16-Apr-14 Ongoing
PRI-724 - NCT01606579 Wnt/β-catenin inhibitors 25-May-12 Completed
BP1001 - NCT02923986 Grb2 5-Oct-16 Withdrawn
Tipifarnib Zarnestra NCT00040105 Farnesyl transferase 21-Jun-02 Completed
Lonafarnib SCH66336 NCT00047502 Farnesyl transferase 9-Oct-02 Completed
Rapamycin Sirolimus NCT00780104 mTOR 27-Oct-08 Completed
RAD001 Everolimus NCT01188889 mTOR 26-Aug-10 Withdrawn
Panobinostat LBH589 NCT00451035 Histone deacetylase 22-Mar-07 Terminated
Azacytidine Vidaza NCT03895671 Hypomethylating agents 29-Mar-19 Ongoing
MK-0457 Tozasertib NCT00405054 Aurora kinase pathway inhibitors 29-Nov-06 Terminated
Venetoclax Venclexta NCT02689440 BCL-2 inhibitors 24-Feb-16 Ongoing
Temsirolimus Torisel NCT00101088 mTOR 10-Jan-05 Terminated
Abemaciclib Verzenio NCT03878524 CDK 4/6 inhibitors 18-Mar-19 Ongoing
Alemtuzumab Lemtrada/campath NCT00626626 CD52 monoclonal antibodies 29-Feb-08 Terminated
Bevacizumab Avastin NCT00023920 VEGF/VEGFR inhibitors 27-Jan-03 Terminated
Blinatumomab Blincyto NCT02790515 Miscellaneous antineoplastic 6-Jun-16 Ongoing
Ipilimumab Yervoy NCT00732186 Anti-CTLA-4 monoclonal antibodies 11-Aug-08 Withdrawn
Nivolumab Opdivo NCT02011945 Anti-PD-1 monoclonal antibodies 16-Dec-13 Completed
Rituximab Rituxan NCT03455517 Antirheumatics, CD20 monoclonal antibodies 6-Mar-18 Terminated

References

  1. MacDonald, B.T.; Tamai, K.; He, X. Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev. Cell 2009, 17, 9–26.
  2. Zhao, C.; Blum, J.; Chen, A.; Kwon, H.Y.; Jung, S.H.; Cook, J.M.; Lagoo, A.; Reya, T. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007, 12, 528–541.
  3. Jamieson, C.H.; Ailles, L.E.; Dylla, S.J.; Muijtjens, M.; Jones, C.; Zehnder, J.L.; Gotlib, J.; Li, K.; Manz, M.G.; Keating, A.; et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 2004, 351, 657–667.
  4. Zhang, B.; Li, M.; McDonald, T.; Holyoake, T.L.; Moon, R.T.; Campana, D.; Shultz, L.; Bhatia, R. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-beta-catenin signaling. Blood 2013, 121, 1824–1838.
  5. Liu, N.; Zang, S.; Liu, Y.; Wang, Y.; Li, W.; Liu, Q.; Ji, M.; Ma, D.; Ji, C. FZD7 regulates BMSCs-mediated protection of CML cells. Oncotarget 2016, 7, 6175–6187.
  6. Zhou, H.; Mak, P.Y.; Mu, H.; Mak, D.H.; Zeng, Z.; Cortes, J.; Liu, Q.; Andreeff, M.; Carter, B.Z. Combined inhibition of beta-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo. Leukemia 2017, 31, 2065–2074.
  7. Hu, Y.; Chen, Y.; Douglas, L.; Li, S. beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia 2009, 23, 109–116.
  8. Hanna, A.; Shevde, L.A. Hedgehog signaling: Modulation of cancer properies and tumor mircroenvironment. Mol. Cancer 2016, 15, 24.
  9. Su, W.; Meng, F.; Huang, L.; Zheng, M.; Liu, W.; Sun, H. Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through beta-catenin signaling. Exp. Hematol. 2012, 40, 418–427.
  10. Dierks, C.; Beigi, R.; Guo, G.R.; Zirlik, K.; Stegert, M.R.; Manley, P.; Trussell, C.; Schmitt-Graeff, A.; Landwerlin, K.; Veelken, H.; et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008, 14, 238–249.
  11. Sadarangani, A.; Pineda, G.; Lennon, K.M.; Chun, H.J.; Shih, A.; Schairer, A.E.; Court, A.C.; Goff, D.J.; Prashad, S.L.; Geron, I.; et al. GLI2 inhibition abrogates human leukemia stem cell dormancy. J. Transl. Med. 2015, 13, 98.
  12. Zhao, C.; Chen, A.; Jamieson, C.H.; Fereshteh, M.; Abrahamsson, A.; Blum, J.; Kwon, H.Y.; Kim, J.; Chute, J.P.; Rizzieri, D.; et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009, 458, 776–779.
  13. Cea, M.; Cagnetta, A.; Cirmena, G.; Garuti, A.; Rocco, I.; Palermo, C.; Pierri, I.; Reverberi, D.; Nencioni, A.; Ballestrero, A.; et al. Tracking molecular relapse of chronic myeloid leukemia by measuring Hedgehog signaling status. Leuk. Lymphoma 2013, 54, 342–352.
  14. Martelli, A.M.; Evangelisti, C.; Chiarini, F.; Grimaldi, C.; Cappellini, A.; Ognibene, A.; McCubrey, J.A. The emerging role of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in normal myelopoiesis and leukemogenesis. Biochim. Biophys. Acta 2010, 1803, 991–1002.
  15. Pellicano, F.; Scott, M.T.; Helgason, G.V.; Hopcroft, L.E.; Allan, E.K.; Aspinall-O'Dea, M.; Copland, M.; Pierce, A.; Huntly, B.J.; Whetton, A.D.; et al. The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors. Stem. Cells 2014, 32, 2324–2337.
  16. Airiau, K.; Mahon, F.X.; Josselin, M.; Jeanneteau, M.; Belloc, F. PI3K/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor. Cell Death Dis. 2013, 4, e827.
  17. Chai, S.K.; Nichols, G.L.; Rothman, P. Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. J. Immunol. 1997, 159, 4720–4728.
  18. Xie, S.; Wang, Y.; Liu, J.; Sun, T.; Wilson, M.B.; Smithgall, T.E.; Arlinghaus, R.B. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene 2001, 20, 6188–6195.
  19. Samanta, A.; Perazzona, B.; Chakraborty, S.; Sun, X.; Modi, H.; Bhatia, R.; Priebe, W.; Arlinghaus, R. Janus kinase 2 regulates Bcr-Abl signaling in chronic myeloid leukemia. Leukemia 2011, 25, 463–472.
  20. Madapura, H.S.; Nagy, N.; Ujvari, D.; Kallas, T.; Krohnke, M.C.L.; Amu, S.; Bjorkholm, M.; Stenke, L.; Mandal, P.K.; McMurray, J.S.; et al. Interferon gamma is a STAT1-dependent direct inducer of BCL6 expression in imatinib-treated chronic myeloid leukemia cells. Oncogene 2017, 36, 4619–4628.
  21. Patel, S.B.; Nemkov, T.; Stefanoni, D.; Benavides, G.A.; Bassal, M.A.; Crown, B.L.; Matkins, V.R.; Camacho, V.; Kuznetsova, V.; Hoang, A.T.; et al. Metabolic alterations mediated by STAT3 promotes drug persistence in CML. Leukemia 2021.
  22. Prost, S.; Relouzat, F.; Spentchian, M.; Ouzegdouh, Y.; Saliba, J.; Massonnet, G.; Beressi, J.P.; Verhoeyen, E.; Raggueneau, V.; Maneglier, B.; et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARgamma agonists. Nature 2015, 525, 380–383.
  23. Zhang, H.; Peng, C.; Hu, Y.; Li, H.; Sheng, Z.; Chen, Y.; Sullivan, C.; Cerny, J.; Hutchinson, L.; Higgins, A.; et al. The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nat. Genet. 2012, 44, 861–871.
  24. Scott, M.T.; Korfi, K.; Saffrey, P.; Hopcroft, L.E.; Kinstrie, R.; Pellicano, F.; Guenther, C.; Gallipoli, P.; Cruz, M.; Dunn, K.; et al. Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition. Cancer Discov. 2016, 6, 1248–1257.
  25. Huang, W.; Luan, C.H.; Hjort, E.E.; Bei, L.; Mishra, R.; Sakamoto, K.M.; Platanias, L.C.; Eklund, E.A. The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia. Leukemia 2016, 30, 1502–1509.
  26. Cheloni, G.; Tanturli, M.; Tusa, I.; Ho DeSouza, N.; Shan, Y.; Gozzini, A.; Mazurier, F.; Rovida, E.; Li, S.; Dello Sbarba, P. Targeting chronic myeloid leukemia stem cells with the hypoxia-inducible factor inhibitor acriflavine. Blood 2017, 130, 655–665.
  27. Zhang, H.; Li, H.; Xi, H.S.; Li, S. HIF1alpha is required for survival maintenance of chronic myeloid leukemia stem cells. Blood 2012, 119, 2595–2607.
  28. Lallemand-Breitenbach, V.; de The, H. PML nuclear bodies. Cold Spring Harb. Perspect. Biol. 2010, 2, a000661.
  29. Kakizuka, A.; Miller, W.H., Jr.; Umesono, K.; Warrell, R.P., Jr.; Frankel, S.R.; Murty, V.V.; Dmitrovsky, E.; Evans, R.M. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 1991, 66, 663–674.
  30. Ito, K.; Bernardi, R.; Morotti, A.; Matsuoka, S.; Saglio, G.; Ikeda, Y.; Rosenblatt, J.; Avigan, D.E.; Teruya-Feldstein, J.; Pandolfi, P.P. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008, 453, 1072–1078.
  31. Hong, C.S.; Ho, W.; Zhang, C.; Yang, C.; Elder, J.B.; Zhuang, Z. LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential. Cancer Biol. Ther. 2015, 16, 821–833.
  32. Neviani, P.; Harb, J.G.; Oaks, J.J.; Santhanam, R.; Walker, C.J.; Ellis, J.J.; Ferenchak, G.; Dorrance, A.M.; Paisie, C.A.; Eiring, A.M.; et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J. Clin. Invest. 2013, 123, 4144–4157.
  33. Lai, D.; Chen, M.; Su, J.; Liu, X.; Rothe, K.; Hu, K.; Forrest, D.L.; Eaves, C.J.; Morin, G.B.; Jiang, X. PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL(+) human leukemia. Sci. Transl. Med. 2018, 10.
  34. Massoumi, R.; Sjolander, A. The role of leukotriene receptor signaling in inflammation and cancer. Sci. World J. 2007, 7, 1413–1421.
  35. Chen, Y.; Hu, Y.; Zhang, H.; Peng, C.; Li, S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat. Genet. 2009, 41, 783–792.
  36. Dolinska, M.; Piccini, A.; Wong, W.M.; Gelali, E.; Johansson, A.S.; Klang, J.; Xiao, P.; Yektaei-Karin, E.; Stromberg, U.O.; Mustjoki, S.; et al. Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34(+)CD38(-) stem and progenitor cells in chronic myeloid leukemia. Biochem. Biophys. Res. Commun. 2017, 490, 378–384.
  37. Rahman, S.; Islam, R. Mammalian Sirt1: Insights on its biological functions. Cell Commun. Signal. 2011, 9, 11.
  38. Yuan, H.; Wang, Z.; Li, L.; Zhang, H.; Modi, H.; Horne, D.; Bhatia, R.; Chen, W. Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 2012, 119, 1904–1914.
  39. Wang, Z.; Yuan, H.; Roth, M.; Stark, J.M.; Bhatia, R.; Chen, W.Y. SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells. Oncogene 2013, 32, 589–598.
  40. Li, L.; Wang, L.; Li, L.; Wang, Z.; Ho, Y.; McDonald, T.; Holyoake, T.L.; Chen, W.; Bhatia, R. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 2012, 21, 266–281.
More
Information
Subjects: Hematology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 276
Revisions: 2 times (View History)
Update Date: 21 Dec 2021
1000/1000