Skip to main content
Log in

The Role of ASXL1/2 and Their Associated Proteins in Malignant Hematopoiesis

  • Cancer and Stem Cells (MD Filippi, Section Editor)
  • Published:
Current Stem Cell Reports Aims and scope Submit manuscript

Abstract

Purpose of the Review

Advances in genomic and epigenetic research have uncovered a central role for aberrant epigenetic regulation in the pathogenesis of myeloid malignancies. In the current review, we summarize the roles of ASXL1/2 and their associated proteins in normal and malignant hematopoiesis.

Recent Findings

ASXL1/2 and their associated proteins, e.g., polycomb repressive complex 2 proteins, play key roles in regulating hematopoietic stem cell (HSC) functions. Genetic studies reveal that ASXL1/2 and their associated proteins play important roles for the establishment and maintenance of the cell fates of HSCs. Alterations of the genes coding ASXL1/2 and their associated proteins lead to the development of hematological malignancies.

Summary

Epigenetic regulation is crucial for normal hematopoiesis. Alteration of multiple epigenetic modifiers contributes to myeloid malignancies. Understanding the molecular mechanisms is critical for further studying ASXL1/2 and their associated proteins in hematopoiesis and developing new therapeutic strategies to treat myeloid malignancies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Greenblatt SM, Nimer SD. Chromatin modifiers and the promise of epigenetic therapy in acute leukemia. Leukemia. 2014;28(7):1396–406. https://doi.org/10.1038/leu.2014.94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Seita J, Weissman IL. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med. 2010;2(6):640–53. https://doi.org/10.1002/wsbm.86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Shih AH, Abdel-Wahab O, Patel JP, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer. 2012;12(9):599–612. https://doi.org/10.1038/nrc3343.

    Article  PubMed  CAS  Google Scholar 

  4. Plass C, Pfister SM, Lindroth AM, Bogatyrova O, Claus R, Lichter P. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat Rev Genet. 2013;14(11):765–80. https://doi.org/10.1038/nrg3554.

    Article  PubMed  CAS  Google Scholar 

  5. Valent P, Kern W, Hoermann G, Milosevic Feenstra JD, Sotlar K, Pfeilstocker M et al. Clonal hematopoiesis with oncogenic potential (chop): separation from CHIP and roads to AML. Int J Mol Sci. 2019;20(3). https://doi.org/10.3390/ijms20030789.

    Article  CAS  Google Scholar 

  6. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8. https://doi.org/10.1038/nm.3733.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87. https://doi.org/10.1056/NEJMoa1409405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98. https://doi.org/10.1056/NEJMoa1408617.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Heumuller A, Wehrle J, Stosch J, Niemoller C, Bleul S, Waterhouse M, et al. Clonal hematopoiesis of indeterminate potential in older patients having received an allogeneic stem cell transplantation from young donors. Bone Marrow Transplant. 2019. https://doi.org/10.1038/s41409-019-0575-4.

  10. Hofmann WK, Koeffler HP. Myelodysplastic syndrome. Annu Rev Med. 2005;56:1–16. https://doi.org/10.1146/annurev.med.56.082103.104704.

    Article  PubMed  CAS  Google Scholar 

  11. Nimer SD. Myelodysplastic syndromes. Blood. 2008;111(10):4841–51. https://doi.org/10.1182/blood-2007-08-078139.

    Article  PubMed  CAS  Google Scholar 

  12. Bejar R, Levine R, Ebert BL. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(5):504–15. https://doi.org/10.1200/JCO.2010.31.1175.

    Article  CAS  Google Scholar 

  13. Schuettengruber B, Bourbon HM, Di Croce L, Cavalli G. Genome regulation by polycomb and trithorax: 70 years and counting. Cell. 2017;171(1):34–57. https://doi.org/10.1016/j.cell.2017.08.002.

    Article  PubMed  CAS  Google Scholar 

  14. Di Carlo V, Mocavini I, Di Croce L. Polycomb complexes in normal and malignant hematopoiesis. J Cell Biol. 2019;218(1):55–69. https://doi.org/10.1083/jcb.201808028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343–9. https://doi.org/10.1038/nature09784.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Hu D, Shilatifard A. Epigenetics of hematopoiesis and hematological malignancies. Genes Dev. 2016;30(18):2021–41. https://doi.org/10.1101/gad.284109.116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Dillon SC, Zhang X, Trievel RC, Cheng X. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 2005;6(8):227. https://doi.org/10.1186/gb-2005-6-8-227.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298(5595):1039–43. https://doi.org/10.1126/science.1076997.

    Article  PubMed  CAS  Google Scholar 

  19. Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell. 2004;15(1):57–67. https://doi.org/10.1016/j.molcel.2004.06.020.

    Article  PubMed  CAS  Google Scholar 

  20. Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 2004;23(20):4061–71. https://doi.org/10.1038/sj.emboj.7600402.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Montgomery ND, Yee D, Chen A, Kalantry S, Chamberlain SJ, Otte AP, et al. The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol. 2005;15(10):942–7. https://doi.org/10.1016/j.cub.2005.04.051.

    Article  PubMed  CAS  Google Scholar 

  22. Woods BA, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Immunol Rev. 2015;263(1):22–35. https://doi.org/10.1111/imr.12246.

    Article  PubMed  CAS  Google Scholar 

  23. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181–5. https://doi.org/10.1038/ng.518.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Sashida G, Iwama A. Multifaceted role of the polycomb-group gene EZH2 in hematological malignancies. Int J Hematol. 2017;105(1):23–30. https://doi.org/10.1007/s12185-016-2124-x.

    Article  PubMed  CAS  Google Scholar 

  25. Iwama A. Polycomb repressive complexes in hematological malignancies. Blood. 2017;130(1):23–9. https://doi.org/10.1182/blood-2017-02-739490.

    Article  PubMed  CAS  Google Scholar 

  26. Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S, et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev. 2012;26(7):651–6. https://doi.org/10.1101/gad.186411.111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Mochizuki-Kashio M, Aoyama K, Sashida G, Oshima M, Tomioka T, Muto T, et al. Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. Blood. 2015;126(10):1172–83. https://doi.org/10.1182/blood-2015-03-634428.

    Article  PubMed  CAS  Google Scholar 

  28. Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu JY, Paulk J, et al. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med. 2016;22(6):632–40. https://doi.org/10.1038/nm.4092.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med. 2013;210(12):2641–59. https://doi.org/10.1084/jem.20131141.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Wang J, Li Z, He Y, Pan F, Chen S, Rhodes S, et al. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice. Blood. 2014;123(4):541–53. https://doi.org/10.1182/blood-2013-05-500272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. •• Yang H, Kurtenbach S, Guo Y, Lohse I, Durante MA, Li J, et al. Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood. 2018;131(3):328–41. https://doi.org/10.1182/blood-2017-06-789669Demonstrates that truncated mutant ASXL1 protein ASXL1aa1–587binds BRD4 and activates gene expression in HSCs, and results in a variety of myeloid malignancies in mice.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. •• Nagase R, Inoue D, Pastore A, Fujino T, Hou HA, Yamasaki N, et al. Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation. J Exp Med. 2018;215(6):1729–47. https://doi.org/10.1084/jem.20171151Demonstrates that physiological expression of mutantAsxl1results in dysfunction of HSCs and promotes susceptibility to myeloid transformation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Uni M, Masamoto Y, Sato T, Kamikubo Y, Arai S, Hara E, et al. Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. Leukemia. 2019;33(1):191–204.

    Article  CAS  Google Scholar 

  34. • Micol JB, Pastore A, Inoue D, Duployez N, Kim E, Lee SC, et al. ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia. Nat Commun. 2017;8:15429. https://doi.org/10.1038/ncomms15429ASXL2 is required for normal hematopoiesis with distinct, non-overlapping effects from ASXL1, andAsxl2loss promoted AML1-ETO leukemogenesis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. • Li J, He F, Zhang P, Chen S, Shi H, Sun Y, et al. Loss of Asxl2 leads to myeloid malignancies in mice. Nat Commun. 2017;8:15456. https://doi.org/10.1038/ncomms15456ASXL2 regulates self-renewal of HSCs and loss ofAsxl2leads to myeloid malignancies.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS, et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science. 2012;337(6101):1541–6. https://doi.org/10.1126/science.1221711.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. LaFave LM, Beguelin W, Koche R, Teater M, Spitzer B, Chramiec A, et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015;21(11):1344–9. https://doi.org/10.1038/nm.3947.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, et al. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J Exp Med. 2013;210(12):2627–39. https://doi.org/10.1084/jem.20131144.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Sashida G, Harada H, Matsui H, Oshima M, Yui M, Harada Y, et al. Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nat Commun. 2014;5:4177. https://doi.org/10.1038/ncomms5177.

    Article  PubMed  CAS  Google Scholar 

  40. Sashida G, Wang C, Tomioka T, Oshima M, Aoyama K, Kanai A, et al. The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. J Exp Med. 2016;213(8):1459–77. https://doi.org/10.1084/jem.20151121.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Shimizu T, Kubovcakova L, Nienhold R, Zmajkovic J, Meyer SC, Hao-Shen H, et al. Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis. J Exp Med. 2016;213(8):1479–96. https://doi.org/10.1084/jem.20151136.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Yang Y, Akada H, Nath D, Hutchison RE, Mohi G. Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm. Blood. 2016;127(26):3410–23. https://doi.org/10.1182/blood-2015-11-679431.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Danis E, Yamauchi T, Echanique K, Zhang X, Haladyna JN, Riedel SS, et al. Ezh2 controls an early hematopoietic program and growth and survival signaling in early T cell precursor acute lymphoblastic leukemia. Cell Rep. 2016;14(8):1953–65. https://doi.org/10.1016/j.celrep.2016.01.064.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Katoh M. Functional and cancer genomics of ASXL family members. Br J Cancer. 2013;109(2):299–306. https://doi.org/10.1038/bjc.2013.281.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Micol JB, Abdel-Wahab O. The role of additional sex combs-like proteins in cancer. Cold Spring Harb Perspect Med. 2016;6(10). https://doi.org/10.1101/cshperspect.a026526.

    Article  CAS  Google Scholar 

  46. Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature. 2010;465(7295):243–7. https://doi.org/10.1038/nature08966.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22(2):180–93. https://doi.org/10.1016/j.ccr.2012.06.032.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. • Inoue D, Fujino T, Sheridan P, Zhang YZ, Nagase R, Horikawa S, et al. A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies. Leukemia. 2018;32(6):1327–37. https://doi.org/10.1038/s41375-018-0083-3First to show that ASXL1 regulates H3K4 methylation through MLL5 in myeloid malignancies.

    Article  PubMed  CAS  Google Scholar 

  49. Li Z, Zhang P, Yan A, Guo Z, Ban Y, Li J, et al. ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis. Sci Adv. 2017;3(1):e1601602. https://doi.org/10.1126/sciadv.1601602.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Zhang P, Chen Z, Li R, Guo Y, Shi H, Bai J, et al. Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates. Cell Discov. 2018;4:4. https://doi.org/10.1038/s41421-017-0004-z.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496–506. https://doi.org/10.1056/NEJMoa1013343.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Thol F, Friesen I, Damm F, Yun H, Weissinger EM, Krauter J, et al. Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(18):2499–506. https://doi.org/10.1200/JCO.2010.33.4938.

    Article  CAS  Google Scholar 

  53. Carbuccia N, Murati A, Trouplin V, Brecqueville M, Adelaide J, Rey J, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia. 2009;23(11):2183–6. https://doi.org/10.1038/leu.2009.141.

    Article  PubMed  CAS  Google Scholar 

  54. Brecqueville M, Rey J, Bertucci F, Coppin E, Finetti P, Carbuccia N, et al. Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. Genes Chromosom Cancer. 2012;51(8):743–55. https://doi.org/10.1002/gcc.21960.

    Article  PubMed  CAS  Google Scholar 

  55. Gelsi-Boyer V, Trouplin V, Adelaide J, Bonansea J, Cervera N, Carbuccia N, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145(6):788–800. https://doi.org/10.1111/j.1365-2141.2009.07697.x.

    Article  PubMed  CAS  Google Scholar 

  56. Gelsi-Boyer V, Trouplin V, Roquain J, Adelaide J, Carbuccia N, Esterni B, et al. ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. Br J Haematol. 2010;151(4):365–75. https://doi.org/10.1111/j.1365-2141.2010.08381.x.

    Article  PubMed  CAS  Google Scholar 

  57. Stieglitz E, Taylor-Weiner AN, Chang TY, Gelston LC, Wang YD, Mazor T, et al. The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet. 2015;47(11):1326–33. https://doi.org/10.1038/ng.3400.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Caye A, Strullu M, Guidez F, Cassinat B, Gazal S, Fenneteau O, et al. Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet. 2015;47(11):1334–40. https://doi.org/10.1038/ng.3420.

    Article  PubMed  CAS  Google Scholar 

  59. Chou WC, Huang HH, Hou HA, Chen CY, Tang JL, Yao M, et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood. 2010;116(20):4086–94. https://doi.org/10.1182/blood-2010-05-283291.

    Article  PubMed  CAS  Google Scholar 

  60. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89. https://doi.org/10.1056/NEJMoa1112304.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Gelsi-Boyer V, Brecqueville M, Devillier R, Murati A, Mozziconacci MJ, Birnbaum D. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol. 2012;5:12. https://doi.org/10.1186/1756-8722-5-12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373(1):35–47. https://doi.org/10.1056/NEJMoa1414799.

    Article  PubMed  CAS  Google Scholar 

  63. Prebet T, Carbuccia N, Raslova H, Favier R, Rey J, Arnoulet C, et al. Concomitant germ-line RUNX1 and acquired ASXL1 mutations in a T-cell acute lymphoblastic leukemia. Eur J Haematol. 2013;91(3):277–9. https://doi.org/10.1111/ejh.12147.

    Article  PubMed  Google Scholar 

  64. Micol JB, Duployez N, Boissel N, Petit A, Geffroy S, Nibourel O, et al. Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations. Blood. 2014;124(9):1445–9. https://doi.org/10.1182/blood-2014-04-571018.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Duployez N, Marceau-Renaut A, Boissel N, Petit A, Bucci M, Geffroy S, et al. Comprehensive mutational profiling of core binding factor acute myeloid leukemia. Blood. 2016;127(20):2451–9. https://doi.org/10.1182/blood-2015-12-688705.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Ward AF, Braun BS, Shannon KM. Targeting oncogenic Ras signaling in hematologic malignancies. Blood. 2012;120(17):3397–406. https://doi.org/10.1182/blood-2012-05-378596.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Zhang P, He F, Bai J, Yamamoto S, Chen S, Zhang L, et al. Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy. J Clin Invest. 2018;128(12):5383–98. https://doi.org/10.1172/JCI121366.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Guo Y, Zhou Y, Yamatomo S, Yang H, Zhang P, Chen S, et al. ASXL1 alteration cooperates with JAK2V617F to accelerate myelofibrosis. Leukemia. 2019;33(5):1287–91. https://doi.org/10.1038/s41375-018-0347-y.

    Article  PubMed  Google Scholar 

  69. Dinan AM, Atkins JF, Firth AE. ASXL gain-of-function truncation mutants: defective and dysregulated forms of a natural ribosomal frameshifting product? Biol Direct. 2017;12(1):24. https://doi.org/10.1186/s13062-017-0195-0.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Inoue D, Matsumoto M, Nagase R, Saika M, Fujino T, Nakayama KI, et al. Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels. Exp Hematol. 2016;44(3):172–6 e1. https://doi.org/10.1016/j.exphem.2015.11.011.

    Article  PubMed  CAS  Google Scholar 

  71. Hoischen A, van Bon BW, Rodriguez-Santiago B, Gilissen C, Vissers LE, de Vries P, et al. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet. 2011;43(8):729–31. https://doi.org/10.1038/ng.868.

    Article  PubMed  CAS  Google Scholar 

  72. Zhang P, Xing C, Rhodes SD, He Y, Deng K, Li Z, et al. Loss of Asxl1 alters self-renewal and cell fate of bone marrow stromal cell, leading to Bohring-Opitz-like syndrome in mice. Stem Cell Rep. 2016;6(6):914–25. https://doi.org/10.1016/j.stemcr.2016.04.013.

    Article  CAS  Google Scholar 

  73. Seiter K, Htun K, Baskind P, Liu Z. Acute myeloid leukemia in a father and son with a germline mutation of ASXL1. Biomarker Res. 2018;6:7. https://doi.org/10.1186/s40364-018-0121-3.

    Article  Google Scholar 

  74. Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer. 2013;13(3):153–9. https://doi.org/10.1038/nrc3459.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Daou S, Barbour H, Ahmed O, Masclef L, Baril C, Sen Nkwe N, et al. Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1. Nat Commun. 2018;9(1):4385. https://doi.org/10.1038/s41467-018-06854-2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Daou S, Hammond-Martel I, Mashtalir N, Barbour H, Gagnon J, Iannantuono NV, et al. The BAP1/ASXL2 histone H2A deubiquitinase complex regulates cell proliferation and is disrupted in cancer. J Biol Chem. 2015;290(48):28643–63. https://doi.org/10.1074/jbc.M115.661553.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Peng H, Prokop J, Karar J, Park K, Cao L, Harbour JW, et al. Familial and somatic BAP1 mutations inactivate ASXL1/2-mediated allosteric regulation of BAP1 deubiquitinase by targeting multiple independent domains. Cancer Res. 2018;78(5):1200–13. https://doi.org/10.1158/0008-5472.CAN-17-2876.

    Article  PubMed  CAS  Google Scholar 

  78. Sahtoe DD, van Dijk WJ, Ekkebus R, Ovaa H, Sixma TK. BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nat Commun. 2016;7:10292. https://doi.org/10.1038/ncomms10292.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Balasubramani A, Larjo A, Bassein JA, Chang X, Hastie RB, Togher SM, et al. Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex. Nat Commun. 2015;6:7307. https://doi.org/10.1038/ncomms8307.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Asada S, Goyama S, Inoue D, Shikata S, Takeda R, Fukushima T, et al. Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis. Nat Commun. 2018;9(1):2733. https://doi.org/10.1038/s41467-018-05085-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Guo Y, Yang H, Chen S, Zhang P, Li R, Nimer SD, et al. Reduced BAP1 activity prevents ASXL1 truncation-driven myeloid malignancy in vivo. Leukemia. 2018;32(8):1834–7. https://doi.org/10.1038/s41375-018-0126-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Hnisz D, Day DS, Young RA. Insulated neighborhoods: structural and functional units of mammalian gene control. Cell. 2016;167(5):1188–200. https://doi.org/10.1016/j.cell.2016.10.024.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Katoh M. Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine. Expert Rev Proteomics. 2015;12(3):317–28. https://doi.org/10.1586/14789450.2015.1033409.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We apologize to the researchers whose work was not cited due to space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Feng-Chun Yang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All reported studies and experiments involving human or animal subjects performed by the authors have been previously published and complied with applicable ethical standards as defined in the Helsinki declaration and its amendments, institutional and national research committee standards, and international/national/institutional guidelines.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Topical Collection on Cancer and Stem Cells

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, P., Xu, M. & Yang, FC. The Role of ASXL1/2 and Their Associated Proteins in Malignant Hematopoiesis. Curr Stem Cell Rep 6, 6–15 (2020). https://doi.org/10.1007/s40778-020-00168-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40778-020-00168-0

Keywords

Navigation