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Epigenetic Abnormalities in Acute Myeloid Leukemia and Leukemia Stem Cells

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Leukemia Stem Cells in Hematologic Malignancies

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1143))

Abstract

Recently advances in cancer genomics revealed the unexpected high frequencies of epigenetic abnormalities in human acute myeloid leukemia (AML). Accumulating data suggest that these leukemia-associated epigenetic factors play critical roles in both normal hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs). In turn, these abnormalities result in susceptibilities of LSC and related diseases to epigenetic inhibitors. In this chapter, we will focus on the mutations of epigenetic factors in AML, their functional roles and mechanisms in normal hematopoiesis and leukemia genesis, especially in LSC, and potential treatment opportunities specifically for AML with epigenetic dysregulations.

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References

  1. Waddington CH (1942) The epigenotype. Endeavour 1:18–20

    Google Scholar 

  2. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11:384–400. https://doi.org/10.1038/nrd3674

    Article  CAS  PubMed  Google Scholar 

  3. Chi P, Allis CD, Wang GG (2010) Covalent histone modifications – miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10:457–469. https://doi.org/10.1038/nrc2876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45. https://doi.org/10.1038/47412

    Article  CAS  PubMed  Google Scholar 

  5. Shi Y et al (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953. https://doi.org/10.1016/j.cell.2004.12.012

    Article  CAS  PubMed  Google Scholar 

  6. Lindroth AM et al (2001) Requirement of CHROMOMETHYLASE3 for maintenance of CpXpG methylation. Science (New York, NY) 292:2077–2080. https://doi.org/10.1126/science.1059745

    Article  CAS  Google Scholar 

  7. Weber M et al (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39:457–466. https://doi.org/10.1038/ng1990

    Article  CAS  PubMed  Google Scholar 

  8. Tamaru H, Selker EU (2001) A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414:277–283. https://doi.org/10.1038/35104508

    Article  CAS  PubMed  Google Scholar 

  9. Cancer Genome Atlas Research, N et al (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368:2059–2074. https://doi.org/10.1056/NEJMoa1301689

    Article  CAS  Google Scholar 

  10. Zhang J et al (2012) The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481:157–163. https://doi.org/10.1038/nature10725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ye H, Wolf RA, Kurz T, Corr PB (1994) Phosphatidic acid increases in response to noradrenaline and endothelin-1 in adult rabbit ventricular myocytes. Cardiovasc Res 28:1828–1834

    Article  CAS  Google Scholar 

  12. Trowbridge JJ, Snow JW, Kim J, Orkin SH (2009) DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 5:442–449. https://doi.org/10.1016/j.stem.2009.08.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Challen GA et al (2011) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44:23–31. https://doi.org/10.1038/ng.1009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Challen GA et al (2014) Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell 15:350–364. https://doi.org/10.1016/j.stem.2014.06.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Moran-Crusio K et al (2011) Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20:11–24. https://doi.org/10.1016/j.ccr.2011.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pan F et al (2017) Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells. Nat Commun 8:15102. https://doi.org/10.1038/ncomms15102

    Article  PubMed  PubMed Central  Google Scholar 

  17. Beerman I et al (2013) Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12:413–425. https://doi.org/10.1016/j.stem.2013.01.017

    Article  CAS  PubMed  Google Scholar 

  18. Buscarlet M et al (2017) DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130:753–762. https://doi.org/10.1182/blood-2017-04-777029

    Article  CAS  PubMed  Google Scholar 

  19. Busque L et al (2012) Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 44:1179–1181. https://doi.org/10.1038/ng.2413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xie M et al (2014) Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20:1472–1478. https://doi.org/10.1038/nm.3733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Park IK et al (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302–305. https://doi.org/10.1038/nature01587

    Article  CAS  PubMed  Google Scholar 

  22. Iwama A et al (2004) Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21:843–851. https://doi.org/10.1016/j.immuni.2004.11.004

    Article  CAS  PubMed  Google Scholar 

  23. Shao L et al (2011) Reactive oxygen species and hematopoietic stem cell senescence. Int J Hematol 94:24–32. https://doi.org/10.1007/s12185-011-0872-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vo LT et al (2018) Regulation of embryonic haematopoietic multipotency by EZH1. Nature 553:506–510. https://doi.org/10.1038/nature25435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mochizuki-Kashio M et al (2011) Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood 118:6553–6561. https://doi.org/10.1182/blood-2011-03-340554

    Article  CAS  PubMed  Google Scholar 

  26. Xie H et al (2014) Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell 14:68–80. https://doi.org/10.1016/j.stem.2013.10.001

    Article  CAS  PubMed  Google Scholar 

  27. Jude CD et al (2007) Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 1:324–337. https://doi.org/10.1016/j.stem.2007.05.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wada T, Koyama D, Kikuchi J, Honda H, Furukawa Y (2015) Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation. Blood 125:3731–3746. https://doi.org/10.1182/blood-2014-11-610907

    Article  CAS  PubMed  Google Scholar 

  29. Stewart MH et al (2015) The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal in mice. Blood 125:2075–2078. https://doi.org/10.1182/blood-2014-08-596734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ntziachristos P et al (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514:513–517. https://doi.org/10.1038/nature13605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Figueroa ME et al (2010) DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17:13–27. https://doi.org/10.1016/j.ccr.2009.11.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chaudry SF, Chevassut TJ (2017) Epigenetic guardian: a review of the DNA methyltransferase DNMT3A in acute myeloid leukaemia and clonal haematopoiesis. Biomed Res Int 2017:5473197

    Article  Google Scholar 

  33. Ley TJ et al (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363:2424–2433

    Article  CAS  Google Scholar 

  34. Ahn J-S et al (2016) DNMT3A R882 mutation with FLT3-ITD positivity is an extremely poor prognostic factor in patients with normal-karyotype acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 22:61–70

    Article  CAS  Google Scholar 

  35. Celik H et al (2015) Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation. Blood 125:619–628

    Article  CAS  Google Scholar 

  36. Mayle A et al (2015) Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood 125:629–638

    Article  CAS  Google Scholar 

  37. Xu J et al (2014) DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells. Proc Natl Acad Sci 111:2620–2625

    Article  CAS  Google Scholar 

  38. Weiskopf K et al (2016) CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest 126:2610–2620. https://doi.org/10.1172/JCI81603

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lu R et al (2016) Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell 30:92–107

    Article  CAS  Google Scholar 

  40. Jeong M et al (2018) Loss of Dnmt3a immortalizes hematopoietic stem cells in vivo. Cell Rep 23:1–10

    Article  CAS  Google Scholar 

  41. Challen GA et al (2012) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44:23

    Article  CAS  Google Scholar 

  42. Ferreira HJ et al (2016) DNMT3A mutations mediate the epigenetic reactivation of the leukemogenic factor MEIS1 in acute myeloid leukemia. Oncogene 35:3079

    Article  CAS  Google Scholar 

  43. Qu Y et al (2014) Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes. Epigenetics 9:1108–1119

    Article  Google Scholar 

  44. Koya J et al (2016) DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation. Nat Commun 7:10924

    Article  CAS  Google Scholar 

  45. Moran-Crusio K et al (2011) Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20:11–24

    Article  CAS  Google Scholar 

  46. Muto H et al (2014) Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice. Blood Cancer J 4:e264

    Article  CAS  Google Scholar 

  47. Rasmussen KD et al (2015) Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis. Genes Dev 29:910–922

    Article  CAS  Google Scholar 

  48. Nakajima H, Kunimoto H (2014) TET2 as an epigenetic master regulator for normal and malignant hematopoiesis. Cancer Sci 105:1093–1099

    Article  CAS  Google Scholar 

  49. Zhao Z et al (2016) The catalytic activity of TET2 is essential for its myeloid malignancy-suppressive function in hematopoietic stem/progenitor cells. Leukemia 30:1784

    Article  CAS  Google Scholar 

  50. Ko M et al (2010) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468:839

    Article  CAS  Google Scholar 

  51. Yamazaki J et al (2012) Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics 7:201–207

    Article  CAS  Google Scholar 

  52. Cimmino L et al (2017) Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170:1079–1095. e1020

    Article  CAS  Google Scholar 

  53. Dang L et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744. https://doi.org/10.1038/nature08617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lu C et al (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474–478. https://doi.org/10.1038/nature10860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ward PS et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234. https://doi.org/10.1016/j.ccr.2010.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ward PS et al (2012) Identification of additional IDH mutations associated with oncometabolite R(−)-2-hydroxyglutarate production. Oncogene 31:2491–2498. https://doi.org/10.1038/onc.2011.416

    Article  CAS  PubMed  Google Scholar 

  57. Sasaki M et al (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488:656–659. https://doi.org/10.1038/nature11323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chen C et al (2013) Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev 27:1974–1985. https://doi.org/10.1101/gad.226613.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. McKenney AS et al (2018) JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Invest 128:789–804. https://doi.org/10.1172/JCI94516

    Article  PubMed  PubMed Central  Google Scholar 

  60. Krivtsov AV, Armstrong SA (2007) MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7:823–833. https://doi.org/10.1038/nrc2253

    Article  CAS  PubMed  Google Scholar 

  61. Bernt KM et al (2011) MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20:66–78. https://doi.org/10.1016/j.ccr.2011.06.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Daigle SR et al (2013) Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122:1017–1025. https://doi.org/10.1182/blood-2013-04-497644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dohner K et al (2002) Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the acute myeloid leukemia study group Ulm. J Clin Oncol 20:3254–3261. https://doi.org/10.1200/JCO.2002.09.088

    Article  CAS  PubMed  Google Scholar 

  64. Pajuelo-Gamez JC et al (2007) MLL amplification in acute myeloid leukemia. Cancer Genet Cytogenet 174:127–131. https://doi.org/10.1016/j.cancergencyto.2006.11.019

    Article  CAS  PubMed  Google Scholar 

  65. Xie H et al (2016) Chronic myelogenous leukemia initiating cells require Polycomb group protein EZH2. Cancer Discov 6:1237–1247. CD-15-1439

    Article  CAS  Google Scholar 

  66. Zhou J et al (2018) PTEN is fundamental for elimination of leukemia stem cells mediated by GSK126 targeting EZH2 in chronic myelogenous leukemia. Clin Cancer Res 24:145–157

    Article  CAS  Google Scholar 

  67. Giambra V et al (2018) Epigenetic restoration of fetal-like IGF1 signaling inhibits leukemia stem cell activity. Cell Stem Cell 23:714–726. e717

    Article  CAS  Google Scholar 

  68. Shi J et al (2013) The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9; Nras G12D acute myeloid leukemia. Oncogene 32:930

    Article  CAS  Google Scholar 

  69. Ueda K et al (2014) Inhibition of histone methyltransferase EZH 2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16. Cancer Sci 105:512–519

    Article  CAS  Google Scholar 

  70. Tanaka S et al (2012) Ezh2 augments leukemogenecity by reinforcing differentiation blockage in acute myeloid leukemia. Blood 120:1107–1117. blood-2011-2011-394932

    Article  CAS  Google Scholar 

  71. Wang C et al (2018) Ezh2 loss propagates hypermethylation at T cell differentiation–regulating genes to promote leukemic transformation. J Clin Invest 128:3872–3886

    Article  Google Scholar 

  72. Kandoth C et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333

    Article  CAS  Google Scholar 

  73. Wong SH et al (2015) The H3K4-methyl epigenome regulates leukemia stem cell oncogenic potential. Cancer Cell 28:198–209

    Article  CAS  Google Scholar 

  74. Chen C et al (2014) MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25:652–665

    Article  Google Scholar 

  75. Liesveld J (2012) Management of AML: who do we really cure? Leuk Res 36:1475–1480

    Article  Google Scholar 

  76. Wang X, Huang S, Chen J-L (2017) Understanding of leukemic stem cells and their clinical implications. Mol Cancer 16:2

    Article  Google Scholar 

  77. Metzeler KH et al (2012) DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia 26:1106

    Article  CAS  Google Scholar 

  78. Pinto A et al (1984) 5-Aza-2′-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemias. Blood 64:922–929

    CAS  PubMed  Google Scholar 

  79. Laurenzana A et al (2009) Inhibition of DNA methyltransferase activates tumor necrosis factor α–induced monocytic differentiation in acute myeloid leukemia cells. Cancer Res 69:55–64

    Article  CAS  Google Scholar 

  80. Curik N et al (2012) 5-azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU. 1 gene and cell differentiation capacity. Leukemia 26:1804

    Article  CAS  Google Scholar 

  81. Liu W, Lee HW, Liu Y, Wang R, Rodgers GP (2010) Olfactomedin 4 is a novel target gene of retinoic acids and 5-aza-2′-deoxycytidine involved in human myeloid leukemia cell growth, differentiation, and apoptosis. Blood 116:4938–4947. blood-2009-2010-246439

    Article  CAS  Google Scholar 

  82. Scott MT et al (2016) Epigenetic reprogramming sensitizes CML stem cells to combined EZH2 and tyrosine kinase inhibition. Cancer Discov 6:1248–1257

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Jing Xu, Xiaohang Hang, Baohong Wu, Chong Chen & Yu Liu

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  1. Jing Xu
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  2. Xiaohang Hang
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  3. Baohong Wu
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  4. Chong Chen
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  5. Yu Liu
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Correspondence to Yu Liu .

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Editors and Affiliations

  1. Medical Research Institute, Wuhan University, Wuhan, Hubei, China

    Haojian Zhang

  2. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Shaoguang Li

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Xu, J., Hang, X., Wu, B., Chen, C., Liu, Y. (2019). Epigenetic Abnormalities in Acute Myeloid Leukemia and Leukemia Stem Cells. In: Zhang, H., Li, S. (eds) Leukemia Stem Cells in Hematologic Malignancies. Advances in Experimental Medicine and Biology, vol 1143. Springer, Singapore. https://doi.org/10.1007/978-981-13-7342-8_8

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