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Emerging concepts of epigenetic dysregulation in hematological malignancies

Abstract

The past decade brought a revolution in understanding of the structure, topology and disease-inducing lesions of RNA and DNA, fueled by unprecedented progress in next-generation sequencing. This technological revolution has also affected understanding of the epigenome and has provided unique opportunities for the analysis of DNA and histone modifications, as well as the first map of the non–protein-coding genome and three-dimensional (3D) chromosomal interactions. Overall, these advances have facilitated studies that combine genetic, transcriptomics and epigenomics data to address a wide range of issues ranging from understanding the role of the epigenome in development to targeting the transcription of noncoding genes in human cancer. Here we describe recent insights into epigenetic dysregulation characteristic of the malignant differentiation of blood stem cells based on studies of alterations that affect epigenetic complexes, enhancers, chromatin, long noncoding RNAs (lncRNAs), RNA splicing, nuclear topology and the 3D conformation of chromatin.

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Figure 1: Genomic alterations that affect gene expression in leukemia.
Figure 2: Targeting the spliceosome in myeloid neoplasms.
Figure 3: Physiological and leukemia-associated functions of epigenetic complexes.
Figure 4: Roles of the cytosine methylation and hydroxymethylation of DNA in normal and malignant hematopoiesis.

References

  1. Feinberg, A.P., Koldobskiy, M.A. & Göndör, A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17, 284–299 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

    CAS  PubMed  Google Scholar 

  3. Whyte, W.A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    CAS  PubMed  Google Scholar 

  5. Gröschel, S. et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157, 369–381 (2014).

    PubMed  Google Scholar 

  6. Yamazaki, H. et al. A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell 25, 415–427 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mansour, M.R. et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346, 1373–1377 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Puente, X.S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).

    CAS  PubMed  Google Scholar 

  9. Herranz, D. et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat. Med. 20, 1130–1137 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, H. et al. NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. Proc. Natl. Acad. Sci. USA 111, 705–710 (2014).

    CAS  PubMed  Google Scholar 

  11. Dekker, J. & Mirny, L. The 3D genome as moderator of chromosomal communication. Cell 164, 1110–1121 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Dixon, J.R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bell, A.C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000).

    CAS  PubMed  Google Scholar 

  15. Hark, A.T. et al. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405, 486–489 (2000).

    CAS  PubMed  Google Scholar 

  16. Zuin, J. et al. Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc. Natl. Acad. Sci. USA 111, 996–1001 (2014).

    CAS  PubMed  Google Scholar 

  17. Trimarchi, T. et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 158, 593–606 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Keim, C., Kazadi, D., Rothschild, G. & Basu, U. Regulation of AID, the B-cell genome mutator. Genes Dev. 27, 1–17 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Qian, J. et al. B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell 159, 1524–1537 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Meng, F.L. et al. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell 159, 1538–1548 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang, Y. et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jan, M. et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl. Med. 4, 149ra118 (2012).

    PubMed  PubMed Central  Google Scholar 

  23. Kon, A. et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat. Genet. 45, 1232–1237 (2013).

    CAS  PubMed  Google Scholar 

  24. Thota, S. et al. Genetic alterations of the cohesin complex genes in myeloid malignancies. Blood 124, 1790–1798 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mazumdar, C. et al. Leukemia-associated cohesin mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation. Cell Stem Cell 17, 675–688 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Mullenders, J. et al. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms. J. Exp. Med. 212, 1833–1850 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Viny, A.D. et al. Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. J. Exp. Med. 212, 1819–1832 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Watrin, E., Kaiser, F.J. & Wendt, K.S. Gene regulation and chromatin organization: relevance of cohesin mutations to human disease. Curr. Opin. Genet. Dev. 37, 59–66 (2016).

    CAS  PubMed  Google Scholar 

  29. Yoshida, K. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64–69 (2011).

    CAS  PubMed  Google Scholar 

  30. Papaemmanuil, E. et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 365, 1384–1395 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Graubert, T.A. et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet. 44, 53–57 (2011).

    PubMed  PubMed Central  Google Scholar 

  32. Wang, L. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497–2506 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Quesada, V. et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 44, 47–52 (2011).

    PubMed  Google Scholar 

  34. Kim, E. et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell 27, 617–630 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, J. et al. Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities. Proc. Natl. Acad. Sci. USA 112, E4726–E4734 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ilagan, J.O. et al. U2AF1 mutations alter splice site recognition in hematological malignancies. Genome Res. 25, 14–26 (2014).

    PubMed  Google Scholar 

  37. Darman, R.B. et al. Cancer-associated SF3B1 hotspot mutations induce cryptic 3′ splice site selection through use of a different branch point. Cell Rep. 13, 1033–1045 (2015).

    CAS  PubMed  Google Scholar 

  38. Alsafadi, S. et al. Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat. Commun. 7, 10615 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Inoue, D., Bradley, R.K. & Abdel-Wahab Spliceosomal gene mutations in myelodysplasia: molecular links to clonal abnormalities of hematopoiesis. Genes Dev. 30, 989–1001 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Daubner, G.M., Cléry, A., Jayne, S., Stevenin, J. & Allain, F.H. A syn-anti conformational difference allows SRSF2 to recognize guanines and cytosines equally well. EMBO J. 31, 162–174 (2012).

    CAS  PubMed  Google Scholar 

  41. Shirai, C.L. et al. Mutant U2AF1 expression alters hematopoiesis and pre-mRNA splicing in vivo. Cancer Cell 27, 631–643 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Papaemmanuil, E. et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627, quiz 3699 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Haferlach, T. et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 28, 241–247 (2014).

    CAS  PubMed  Google Scholar 

  44. Isono, K., Mizutani-Koseki, Y., Komori, T., Schmidt-Zachmann, M.S. & Koseki, H. Mammalian polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1. Genes Dev. 19, 536–541 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kfir, N. et al. SF3B1 association with chromatin determines splicing outcomes. Cell Rep. 11, 618–629 (2015).

    CAS  PubMed  Google Scholar 

  46. Garding, A. et al. Epigenetic upregulation of lncRNAs at 13q14.3 in leukemia is linked to the in cis downregulation of a gene cluster that targets NF-kB. PLoS Genet. 9, e1003373 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Stilgenbauer, S. et al. Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Oncogene 16, 1891–1897 (1998).

    CAS  PubMed  Google Scholar 

  48. Klein, U. et al. The DLEU2/miR-15a/16–1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17, 28–40 (2010).

    CAS  PubMed  Google Scholar 

  49. Yildirim, E. et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152, 727–742 (2013).

    CAS  PubMed  Google Scholar 

  50. Luger, K., Mäder, A.W., Richmond, R.K., Sargent, D.F. & Richmond, T.J. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251–260 (1997).

    CAS  PubMed  Google Scholar 

  51. Kornberg, R.D. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868–871 (1974).

    CAS  PubMed  Google Scholar 

  52. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Voigt, P., Tee, W.W. & Reinberg, D. A double take on bivalent promoters. Genes Dev. 27, 1318–1338 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    CAS  PubMed  Google Scholar 

  55. Ernst, T. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42, 722–726 (2010).

    CAS  PubMed  Google Scholar 

  56. Morin, R.D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Béguelin, W. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).

    PubMed  PubMed Central  Google Scholar 

  58. McCabe, M.T. et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc. Natl. Acad. Sci. USA 109, 2989–2994 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sneeringer, C.J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl. Acad. Sci. USA 107, 20980–20985 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Yap, D.B. et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451–2459 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat. Genet. 46, 176–181 (2014).

    CAS  PubMed  Google Scholar 

  62. Ntziachristos, P. et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18, 298–301 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Simon, C. et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev. 26, 651–656 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Danis, E. et al. Ezh2 controls an early hematopoietic program and growth and survival signaling in early T cell precursor acute lymphoblastic leukemia. Cell Rep. 14, 1953–1965 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Shi, J. et al. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras(G12D) acute myeloid leukemia. Oncogene 32, 930–938 (2013).

    CAS  PubMed  Google Scholar 

  67. Neff, T. et al. Polycomb repressive complex 2 is required for MLL-AF9 leukemia. Proc. Natl. Acad. Sci. USA 109, 5028–5033 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Velichutina, I. et al. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116, 5247–5255 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Chen, H. et al. Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 23, 975–985 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. van Kruijsbergen, I., Hontelez, S. & Veenstra, G.J. Recruiting polycomb to chromatin. Int. J. Biochem. Cell Biol. 67, 177–187 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Shields, B.J. et al. Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a. Genes Dev. 30, 78–91 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lubitz, S., Glaser, S., Schaft, J., Stewart, A.F. & Anastassiadis, K. Increased apoptosis and skewed differentiation in mouse embryonic stem cells lacking the histone methyltransferase Mll2. Mol. Biol. Cell 18, 2356–2366 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang, P. et al. Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol. Cell. Biol. 29, 6074–6085 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Shilatifard, A., Lane, W.S., Jackson, K.W., Conaway, R.C. & Conaway, J.W. An RNA polymerase II elongation factor encoded by the human ELL gene. Science 271, 1873–1876 (1996).

    CAS  PubMed  Google Scholar 

  77. Bernt, K.M. & Armstrong, S.A. A role for DOT1L in MLL-rearranged leukemias. Epigenomics 3, 667–670 (2011).

    CAS  PubMed  Google Scholar 

  78. Bernt, K.M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Tan, J. et al. CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell 20, 563–575 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    CAS  PubMed  Google Scholar 

  81. Allis, C.D. et al. New nomenclature for chromatin-modifying enzymes. Cell 131, 633–636 (2007).

    CAS  PubMed  Google Scholar 

  82. Harris, W.J. et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473–487 (2012).

    CAS  PubMed  Google Scholar 

  83. Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605–611 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Yatim, A. et al. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol. Cell 48, 445–458 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, Y. et al. Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis. Oncogene 31, 5007–5018 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Whetstine, J.R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

    CAS  PubMed  Google Scholar 

  87. Agger, K. et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449, 731–734 (2007).

    CAS  PubMed  Google Scholar 

  88. De Santa, F. et al. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130, 1083–1094 (2007).

    CAS  PubMed  Google Scholar 

  89. Lan, F. et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 449, 689–694 (2007).

    CAS  PubMed  Google Scholar 

  90. Lee, M.G. et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318, 447–450 (2007).

    CAS  PubMed  Google Scholar 

  91. Jepsen, K. et al. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450, 415–419 (2007).

    CAS  PubMed  Google Scholar 

  92. Hong, S. et al. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc. Natl. Acad. Sci. USA 104, 18439–18444 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Greenfield, A. et al. The UTX gene escapes X inactivation in mice and humans. Hum. Mol. Genet. 7, 737–742 (1998).

    CAS  PubMed  Google Scholar 

  94. Van der Meulen, J. et al. The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood 125, 13–21 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Benyoucef, A. et al. UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes Dev. 30, 508–521 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ntziachristos, P. et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514, 513–517 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Guo, J.U., Su, Y., Zhong, C., Ming, G.L. & Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423–434 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Ji, H. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Hogart, A. et al. Genome-wide DNA methylation profiles in hematopoietic stem and progenitor cells reveal overrepresentation of ETS transcription factor binding sites. Genome Res. 22, 1407–1418 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Bock, C. et al. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol. Cell 47, 633–647 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Figueroa, M.E. et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17, 13–27 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Ley, T.J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Smith, A.E. et al. Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood 116, 3923–3932 (2010).

    CAS  PubMed  Google Scholar 

  104. Mardis, E.R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Grossmann, V. et al. The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. Genes Chromosom. Cancer 52, 410–422 (2013).

    CAS  PubMed  Google Scholar 

  106. Shlush, L.I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Li, Z. et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118, 4509–4518 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. An, J. et al. Acute loss of TET function results in aggressive myeloid cancer in mice. Nat. Commun. 6, 10071 (2015).

    CAS  PubMed  Google Scholar 

  110. Lobry, C. et al. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J. Exp. Med. 210, 301–319 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Shih, A.H. et al. Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell 27, 502–515 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Cimmino, L. et al. TET1 is a tumor suppressor of hematopoietic malignancy. Nat. Immunol. 16, 653–662 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ficz, G. et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398–402 (2011).

    CAS  PubMed  Google Scholar 

  114. Pastor, W.A. et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473, 394–397 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Chen, C. et al. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev. 27, 1974–1985 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Meyer, S.E. et al. DNMT3A haploinsufficiency transforms FLT3ITD myeloproliferative disease into a rapid, spontaneous, and fully penetrant acute myeloid leukemia. Cancer Discov. 6, 501–515 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Chen, Q., Chen, Y., Bian, C., Fujiki, R. & Yu, X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561–564 (2013).

    CAS  PubMed  Google Scholar 

  120. Vella, P. et al. Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol. Cell 49, 645–656 (2013).

    CAS  PubMed  Google Scholar 

  121. Flavahan, W.A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).

    CAS  PubMed  Google Scholar 

  122. Bitler, B.G. et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21, 231–238 (2015).

    CAS  PubMed  Google Scholar 

  123. Kim, K.H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. McCabe, M.T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).

    CAS  PubMed  Google Scholar 

  125. Knutson, S.K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890–896 (2012).

    CAS  PubMed  Google Scholar 

  126. Chen, C.W. et al. DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat. Med. 21, 335–343 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Daigle, S.R. et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53–65 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).

    CAS  PubMed  Google Scholar 

  129. Delmore, J.E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).

    PubMed  PubMed Central  Google Scholar 

  131. Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the members of all laboratories, and M. Guillamot and L. Cimmino for comments and illustrations. Supported by the US National Institutes of Health (1K08CA160647-01 and R01 HL128239 for the Abdel-Wahab laboratory; and RO1CA133379, RO1CA105129, RO1CA149655, 5RO1CA173636, 1RO1CA194923 and R01 CA190509 for the Aifantis laboratory); the National Cancer Institute (R00CA188293-02), the American Society of Hematology, the Zell Foundation and the Chicago Region Physical Science-Oncology Center (all for the Ntziachristos laboratory); the Department of Defense (BM150092 and W81XWH-12-1-0041), the Damon Runyon Foundation, the Edward P. Evans Foundation, the V Foundation, the Starr Foundation, the Josie Robertson Investigator Program and the Pershing Square Sohn Cancer Research Alliance (all for the Abdel-Wahab laboratory); and the Leukemia and Lymphoma Society, the NYSTEM program of the New York State Health Department, The William Lawrence and Blanche Hughes Foundation and the Chemotherapy Foundation (all for the Aifantis laboratory).

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Correspondence to Panagiotis Ntziachristos, Omar Abdel-Wahab or Iannis Aifantis.

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Ntziachristos, P., Abdel-Wahab, O. & Aifantis, I. Emerging concepts of epigenetic dysregulation in hematological malignancies. Nat Immunol 17, 1016–1024 (2016). https://doi.org/10.1038/ni.3517

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