Epigenetics of hematopoiesis and hematological malignancies

Genes and Development

Volumn 30, Issue 18, 2016, Pages 2021-2041

  Hu, Deqing ^a   Shilatifard, Ali ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Chromatin; Epigenetics; Hematopoiesis; Histone

Indexed keywords

DNA; HISTONE; HISTONE METHYLTRANSFERASE; LYSINE; MIXED LINEAGE LEUKEMIA PROTEIN; POLYCOMB GROUP PROTEIN;

CARCINOGENESIS; DNA METHYLATION; ENHANCER REGION; EPIGENETICS; GENE MUTATION; HEMATOLOGIC MALIGNANCY; HEMATOPOIESIS; HISTONE METHYLATION; HUMAN; LEUKEMIA; MOLECULAR GENETICS; MOLECULAR PATHOLOGY; NONHUMAN; PRIORITY JOURNAL; REVIEW; TRANSCRIPTION ELONGATION; ANIMAL; CHROMATIN; ENZYMOLOGY; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETICS; HEMATOLOGIC DISEASE; MUTATION; PATHOPHYSIOLOGY;

ANIMALS; CHROMATIN; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HEMATOLOGIC NEOPLASMS; HEMATOPOIESIS; HUMANS; MUTATION;

EID: 84990989710     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.284109.116     Document Type: Review

References (249)

1. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, et al. 2009. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114: 144-147.
2. Abdel-Wahab O, Pardanani A, Patel J, Wadleigh M, Lasho T, Heguy A, Beran M, Gilliland DG, Levine RL, Tefferi A. 2011. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Leukemia 25: 1200-1202.
3. Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH, Pandey S, Patel JP, Chung YR, Koche R, et al. 2012. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 22: 180-193.
4. Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K. 2007. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449: 731-734.
5. Akasaka T, Tsuji K, Kawahira H, Kanno M, Harigaya K, Hu L, Ebihara Y, Nakahata T, Tetsu O, Taniguchi M, et al. 1997. The role of mel-18, a mammalian Polycomb group gene, during IL-7-dependent proliferation of lymphocyte precursors. Immunity 7: 135-146.
6. Andersen EF, Carey JC, Earl DL, Corzo D, Suttie M, Hammond P, South ST. 2014. Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn syndrome. Eur J Hum Genet 22: 464-470.
7. Aranda S, Mas G, Di Croce L. 2015. Regulation of gene transcription by Polycomb proteins. Sci Adv 1: e1500737.
8. Baron MH, Isern J, Fraser ST. 2012. The embryonic origins of erythropoiesis in mammals. Blood 119: 4828-4837.
9. BeguelinW, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, Shen H, Yang SN,Wang L, Ezponda T, et al. 2013. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23: 677-692.
10. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, et al. 2011. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364: 2496-2506.
11. Benyoucef A, Palii CG, Wang C, Porter CJ, Chu A, Dai F, Tremblay V, Rakopoulos P, Singh K, Huang S, et al. 2016. UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes Dev 30: 508-521.
12. Berg T, Thoene S, Yap D, Wee T, Schoeler N, Rosten P, Lim E, Bilenky M, Mungall AJ, Oellerich T, et al. 2014. A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis. Blood 123: 3914-3924.
13. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. 2009. An operational definition of epigenetics. Genes Dev 23: 781-783.
14. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, Feng Z, Punt N, Daigle A, Bullinger L, et al. 2011. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20: 66-78.
15. Blackledge NP, Farcas AM, Kondo T, King HW, McGouran JF, Hanssen LL, Ito S, Cooper S, Kondo K, Koseki Y, et al. 2014. Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell 157: 1445-1459.
16. Bock C, Beerman I, Lien WH, Smith ZD, Gu H, Boyle P, Gnirke A, Fuchs E, Rossi DJ, Meissner A. 2012. DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol Cell 47: 633-647.
17. Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, Purohit T, Malik B, Zhao T,Wang J, et al. 2015. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell 27: 589-602.
18. Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, Creaney J, Lake RA, Zakowski MF, Reva B, et al. 2011. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 43: 668-672.
19. Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS,Wernig M, Tajonar A, Ray MK, et al. 2006. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441: 349-353.
20. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. 2003. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22: 5323-5335.
21. Brien GL, Valerio DG, Armstrong SA. 2016. Exploiting the epigenome to control cancer-promoting gene-expression programs. Cancer Cell 29: 464-476.
22. Broske AM, Vockentanz L, Kharazi S, Huska MR, Mancini E, Scheller M, Kuhl C, Enns A, Prinz M, Jaenisch R, et al. 2009. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet 41: 1207-1215.
23. Buske C, Humphries RK. 2000. Homeobox genes in leukemogenesis. Int J Hematol 71: 301-308.
24. Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, Mollica L, Li J, Viale A, Heguy A, et al. 2012. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 44: 1179-1181.
25. Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, George L, Alberghini F, Ferrarini L, Talukder AK, et al. 2013. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest 123: 5009-5022.
26. Cai SF, Chen CW, Armstrong SA. 2015. Drugging chromatin in cancer: recent advances and novel approaches. Mol Cell 60: 561-570.
27. Cales C, Roman-Trufero M, Pavon L, Serrano I, Melgar T, Endoh M, Perez C, Koseki H, Vidal M. 2008. Inactivation of the polycomb group protein Ring1B unveils an antiproliferative role in hematopoietic cell expansion and cooperation with tumorigenesis associated with Ink4a deletion. Mol Cell Biol 28: 1018-1028.
28. Caligiuri MA, Schichman SA, Strout MP, Mrozek K, Baer MR, Frankel SR, Barcos M, Herzig GP, Croce CM, Bloomfield CD. 1994. Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. Cancer Res 54: 370-373.
29. Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F, Knuutila S, Mrozek K, Oberkircher AR, Marcucci G, et al. 1998. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res 58: 55-59.
30. Cao R,Wang L,Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. 2002. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298: 1039-1043.
31. Cao F, Townsend EC, Karatas H, Xu J, Li L, Lee S, Liu L, Chen Y, Ouillette P, Zhu J, et al. 2014. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol Cell 53: 247-261.
32. Caslini C, Yang Z, El-Osta M, Milne TA, Slany RK, Hess JL. 2007. Interaction of MLL amino terminal sequences with menin is required for transformation. Cancer Res 67: 7275-7283.
33. Cerveira N, Correia C, Doria S, Bizarro S, Rocha P, Gomes P, Torres L, Norton L, Borges BS, Castedo S, et al. 2003. Frequency of NUP98-NSD1 fusion transcript in childhood acute myeloid leukaemia. Leukemia 17: 2244-2247.
34. Challen GA, Sun D, Jeong M, Luo M, Jelinek J, Berg JS, Bock C, Vasanthakumar A, Gu H, Xi Y, et al. 2012. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44: 23-31.
35. Challen GA, Sun D, Mayle A, Jeong M, Luo M, Rodriguez B, Mallaney C, Celik H, Yang L, Xia Z, et al. 2014. Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell 15: 350-364.
36. Chang MJ, Wu H, Achille NJ, Reisenauer MR, Chou CW, Zeleznik-Le NJ, Hemenway CS, ZhangW. 2010. Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes. Cancer Res 70: 10234-10242.
37. Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, Shroff AS, Dickins RA, Vakoc CR, Bradner JE, et al. 2014. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25: 652-665.
38. Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL. 1998. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92: 3025-3034.
39. Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, et al. 2007. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem 282: 20395-20406.
40. Chowdhury M, Mihara K, Yasunaga S, Ohtaki M, Takihara Y, Kimura A. 2007. Expression of Polycomb-group (PcG) protein BMI-1 predicts prognosis in patients with acute myeloid leukemia. Leukemia 21: 1116-1122.
41. Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R. 2014. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci 111: 2548-2553.
42. Core N, Bel S, Gaunt SJ, Aurrand-Lions M, Pearce J, Fisher A, Djabali M. 1997. Altered cellular proliferation and mesodermpatterning in Polycomb-M33-deficient mice. Development 124: 721-729.
43. Creyghton MP, Cheng AW,Welstead GG, Kooistra T, Carey BW, Steine EJ, Hanna J, Lodato MA, Frampton GM, Sharp PA, et al. 2010. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci 107: 21931-21936.
44. Cullen SM, Mayle A, Rossi L, Goodell MA. 2014. Hematopoietic stem cell development: an epigenetic journey. Curr Topics Dev Biol 107: 39-75.
45. Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM. 1982. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci 79: 7824-7827.
46. Danis E, Yamauchi T, Echanique K, Zhang X, Haladyna JN, Riedel SS, Zhu N, Xie H, Orkin SH, Armstrong SA, et al. 2016. Ezh2 controls an early hematopoietic program and growth and survival signaling in early T cell precursor acute lymphoblastic leukemia. Cell Rep 14: 1953-1965.
47. del Mar Lorente M, Marcos-Gutierrez C, Perez C, Schoorlemmer J, Ramirez A, Magin T, Vidal M. 2000. Loss- and gain-of-function mutations showa polycomb group function for Ring1A in mice. Development 127: 5093-5100.
48. Deshpande AJ, Chen L, Fazio M, Sinha AU, Bernt KM, Banka D, Dias S, Chang J, Olhava EJ, Daigle SR, et al. 2013. Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. Blood 121: 2533-2541.
49. Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS, Kirkpatrick DS, Pham VC, Lill JR, Bakalarski CE, et al. 2012. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337: 1541-1546.
50. Ding X, Lin Q, Ensenat-Waser R, Rose-John S, Zenke M. 2012. Polycomb group protein Bmi1 promotes hematopoietic cell development from embryonic stem cells. Stem Cells Dev 21: 121-132.
51. Dorsett D. 1999. Distant liaisons: long-range enhancer-promoter interactions in Drosophila. Curr Opin Genet Dev 9: 505-514.
52. Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG. 2006. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol 13: 713-719.
53. Douglas J, Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M, Tomkins S, Hughes HE, Cole TR, Rahman N. 2003. NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. Am J Hum Genet 72: 132-143.
54. Doulatov S, Notta F, Laurenti E, Dick JE. 2012. Hematopoiesis: a human perspective. Cell Stem Cell 10: 120-136.
55. Ernst P, Mabon M, Davidson AJ, Zon LI, Korsmeyer SJ. 2004. An Mll-dependent Hox program drives hematopoietic progenitor expansion. Curr Biol 14: 2063-2069.
56. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, JonesAV, Waghorn K, Zoi K, Ross FM, Reiter A, et al. 2010. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 42: 722-726.
57. Etchin J, Kanki JP, Look AT. 2011. Zebrafish as a model for the study of human cancer. Methods Cell Biol 105: 309-337.
58. Feng Y, Yang Y, Ortega MM, Copeland JN, Zhang M, Jacob JB, Fields TA, Vivian JL, Fields PE. 2010. Early mammalian erythropoiesis requires the Dot1L methyltransferase. Blood 116: 4483-4491.
59. Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, Schifano E, Booth J, van Putten W, Skrabanek L, et al. 2010. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17: 13-27.
60. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, et al. 2010. Selective inhibition of BET bromodomains. Nature 468: 1067-1073.
61. FischleW, Wang Y, Jacobs SA, Kim Y, Allis CD, Khorasanizadeh S. 2003. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev 17: 1870-1881.
62. Gan T, Jude CD, Zaffuto K, Ernst P. 2010. Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis. Leukemia 24: 1732-1741.
63. Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D. 2012. PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol Cell 45: 344-356.
64. Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL, Kela I, Hopmans ES, Myklebust JH, Ji H, et al. 2013. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood 121: 1604-1611.
65. Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ, Irish J, Stehr H, Vicente-Duenas C, Romero-Camarero I, et al. 2015. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci 112: E1116-E1125.
66. Grembecka J, He SH, Shi AB, Purohit T, Muntean AG, Sorenson RJ, Showalter HD, Murai MJ, Belcher AM, Hartley T, et al. 2012. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat Chem Biol 8: 277-284.
67. Groschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BA, Erpelinck C, van der Velden VH, Havermans M, Avellino R, van Lom K, et al. 2014. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157: 369-381.
68. Grossmann V, Kohlmann A, Zenger M, Schindela S, Eder C, Weissmann S, Schnittger S, Kern W, Muller MC, Hochhaus A, et al. 2011. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia 25: 557-560.
69. Guglielmelli P, Biamonte F, Score J, Hidalgo-Curtis C, Cervantes F, Maffioli M, Fanelli T, Ernst T, Winkelman N, Jones AV, et al. 2011. EZH2 mutational status predicts poor survival in myelofibrosis. Blood 118: 5227-5234.
70. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM. 2010. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330: 1410-1413.
71. Hashimoto H, Liu Y, Upadhyay AK, Chang Y, Howerton SB, Vertino PM, Zhang X, Cheng X. 2012. Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res 40: 4841-4849.
72. He YF, Li BZ, Li Z, Liu P,Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, et al. 2011. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333: 1303-1307.
73. Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA, et al. 2007. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39: 311-318.
74. Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, Ye Z, Lee LK, Stuart RK, Ching CW, et al. 2009. Histone modifications at human enhancers reflect global celltype-specific gene expression. Nature 459: 108-112.
75. Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L,Wendorff AA, Xu L, Castillo-Martin M, Llobet-Navas D, Cordon-Cardo C, et al. 2014. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat Med 20: 1130-1137.
76. Herrera-Merchan A, Arranz L, Ligos JM, de Molina A, Dominguez O, Gonzalez S. 2012. Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat Commun 3: 623.
77. Herz HM, Mohan M, Garruss AS, Liang K, Takahashi YH, Mickey K, Voets O, Verrijzer CP, Shilatifard A. 2012. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev 26: 2604-2620.
78. Herz HM, Hu D, Shilatifard A. 2014. Enhancer malfunction in cancer. Mol Cell 53: 859-866.
79. Hess JL, Yu BD, Li B, Hanson R, Korsmeyer SJ. 1997. Defects in yolk sac hematopoiesis in Mll-null embryos. Blood 90: 1799-1806.
80. Hidalgo I, Herrera-Merchan A, Ligos JM, Carramolino L, Nunez J, Martinez F, Dominguez O, Torres M, Gonzalez S. 2012. Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. Cell Stem Cell 11: 649-662.
81. Hsieh JJ, Cheng EH, Korsmeyer SJ. 2003. Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression. Cell 115: 293-303.
82. Hu D, Gao X, Morgan MA, Herz HM, Smith ER, Shilatifard A. 2013a. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol Cell Biol 33: 4745-4754.
83. Hu D, Smith ER, Garruss AS, Mohaghegh N, Varberg JM, Lin C, Jackson J, Gao X, Saraf A, Florens L, et al. 2013b. The little elongation complex functions at initiation and elongation phases of snRNA gene transcription. Mol Cell 51: 493-505.
84. Huang H, Jiang X, Li Z, Li Y, Song CX, He C, Sun M, Chen P, Gurbuxani S, Wang J, et al. 2013a. TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc Natl Acad Sci 110: 11994-11999.
85. Huang Z, WuH, Chuai S, Xu F, Yan F, Englund N, Wang Z, Zhang H, Fang M, WangY, et al. 2013b. NSD2 is recruited through its PHD domain to oncogenic gene loci to drive multiple myeloma. Cancer Res 73: 6277-6288.
86. Inoue D, Kitaura J, Togami K, Nishimura K, Enomoto Y, Uchida T, Kagiyama Y, Kawabata KC, Nakahara F, Izawa K, et al. 2013. Myelodysplastic syndromes are induced by histone methylation-altering ASXL1 mutations. J Clin Invest 123: 4627-4640.
87. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y. 2011. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333: 1300-1303.
88. Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H, Ema H, Kamijo T, Katoh-Fukui Y, Koseki H, et al. 2004. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21: 843-851.
89. Iyer LM, Tahiliani M, Rao A, Aravind L. 2009. Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle 8: 1698-1710.
90. Jaffe JD, Wang Y, Chan HM, Zhang J, Huether R, Kryukov GV, Bhang HE, Taylor JE, Hu M, Englund NP, et al. 2013. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat Genet 45: 1386-1391.
91. Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, O’Keefe CL, Ganetzky R, McDevitt MA, Maciejewski JP. 2009. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 113: 6403-6410.
92. Jankowska AM, Makishima H, Tiu RV, Szpurka H, Huang Y, Traina F, Visconte V, Sugimoto Y, Prince C, O’Keefe C, et al. 2011. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 118: 3932-3941.
93. Ji H, Ehrlich LI, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Irizarry RA, Kim K, et al. 2010. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467: 338-342.
94. Jones PA, Liang G. 2009. Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 10: 805-811.
95. Jude CD, Climer L, Xu D, Artinger E, Fisher JK, Ernst P. 2007. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 1: 324-337.
96. Kajiume T, Ninomiya Y, Ishihara H, Kanno R, Kanno M. 2004. Polycomb group gene mel-18 modulates the self-renewal activity and cell cycle status of hematopoietic stem cells. Exp Hematol 32: 571-578.
97. Kalb R, Latwiel S, Baymaz HI, JansenPW, MullerCW, Vermeulen M, Muller J. 2014. Histone H2A monoubiquitination promotes histone H3 methylation in Polycomb repression. Nat Struct Mol Biol 21: 569-571.
98. Kamminga LM, Bystrykh LV, Boer AC, Houwer S, Douma J, Weersing E, Dontje B, de Haan G. 2006. The polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107: 2170-2179.
99. Kanda H, Nguyen A, Chen L, Okano H, Hariharan IK. 2013. The Drosophila ortholog of MLL3 and MLL4, trithorax related, functions as a negative regulator of tissue growth. Mol Cell Biol 33: 1702-1710.
100. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, et al. 2013. Mutational landscape and significance across 12 major cancer types. Nature 502: 333-339.
101. Karatas H, Townsend EC, Cao F, Chen Y, Bernard D, Liu L, Lei M, Dou Y, Wang S. 2013. High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction. J Am Chem Soc 135: 669-682.
102. Kim SJ, Zhao H, Hardikar S, Singh AK, Goodell MA, Chen T. 2013. A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood 122: 4086-4089.
103. Klauke K, RadulovicV, Broekhuis M,Weersing E, Zwart E, Olthof S, Ritsema M, Bruggeman S, Wu X, Helin K, et al. 2013. Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat Cell Biol 15: 353-362.
104. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, et al. 2003. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci 100: 11606-11611.
105. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J, et al. 2012. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 8: 890-896.
106. Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A. 2011. Teneleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci 108: 14566-14571.
107. Kondo Y, Shen L, Cheng AS, Ahmed S, Boumber Y, Charo C, Yamochi T, Urano T, Furukawa K, Kwabi-Addo B, et al. 2008. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet 40: 741-750.
108. Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU, Xia X, Jesneck J, Bracken AP, Silverman LB, et al. 2008. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 14: 355-368.
109. Kroeze LI, Nikoloski G, da Silva-Coelho P, van Hoogen P, Stevens-Linders E, Kuiper RP, Schnittger S, Haferlach T, Pahl HL, van der Reijden BA, et al. 2012. Genetic defects in PRC2 components other than EZH2 are not common in myeloid malignancies. Blood 119: 1318-1319.
110. Krogan NJ, Dover J, Khorrami S, Greenblatt JF, Schneider J, Johnston M, Shilatifard A. 2002. COMPASS, a histone H3 (lysine 4) methyltransferase required for telomeric silencing of gene expression. J Biol Chem 277: 10753-10755.
111. Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G. 1998. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J 17: 3714-3725.
112. Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, Presser A, Nusbaum C, Xie X, Chi AS, et al. 2008. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet 4: e1000242.
113. KuhnMW, Hadler MJ, Daigle SR, Koche RP, Krivtsov AV, Olhava EJ, Caligiuri MA, Huang G, Bradner JE, Pollock RM, et al. 2015. MLL partial tandem duplication leukemia cells are sensitive to small molecule DOT1L inhibition. Haematologica 100: e190-e193.
114. Kuo AJ, Cheung P, Chen K, Zee BM, Kioi M, Lauring J, Xi Y, Park BH, Shi X, Garcia BA, et al. 2011. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol Cell 44: 609-620.
115. LaFave LM, BeguelinW, Koche R, Teater M, Spitzer B, Chramiec A, Papalexi E, Keller MD, Hricik T, Konstantinoff K, et al. 2015. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med 21: 1344-1349.
116. LaFave LM, BeguelinW, Koche R, Teater M, Spitzer B, Chramiec A, Papalexi E, Keller MD, Hricik T, Konstantinoff K, et al. 2016. Reply to ‘Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status’. Nat Med 22: 578-579.
117. Lan F, Bayliss PE, Rinn JL, Whetstine JR,Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, et al. 2007. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 449: 689-694.
118. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, Meyerson M, Gabriel SB, Lander ES, Getz G. 2014. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505: 495-501.
119. Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R. 2007. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318: 447-450.
120. Lee JE, Wang C, Xu S, Cho YW,Wang L, Feng X, Baldridge A, Sartorelli V, Zhuang L, Peng W, et al. 2013. H3K4 mono- and dimethyltransferase MLL4 is required for enhancer activation during cell differentiation. Elife 2: e01503.
121. Lee SC, Miller S, Hyland C, Kauppi M, Lebois M, Di Rago L, Metcalf D, Kinkel SA, Josefsson EC, Blewitt ME, et al. 2015. Polycomb repressive complex 2 component Suz12 is required for hematopoietic stem cell function and lymphopoiesis. Blood 126: 167-175.
122. Lessard J, Sauvageau G. 2003. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423: 255-260.
123. Lewis EB. 1978. Agene complex controlling segmentation in Drosophila. Nature 276: 565-570.
124. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, et al. 2010. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363: 2424-2433.
125. Li L, Clevers H. 2010. Coexistence of quiescent and active adult stem cells in mammals. Science 327: 542-545.
126. Li X, Gonzalez ME, Toy K, Filzen T, Merajver SD, Kleer CG. 2009a. Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia. Am J Pathol 175: 1246-1254.
127. Li Y, Trojer P, Xu CF, Cheung P, Kuo A, Drury WJ III, Qiao Q, Neubert TA, Xu RM, Gozani O, et al. 2009b. The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J Biol Chem 284: 34283-34295.
128. Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, Washburn MP, Conaway JW, Conaway RC, Shilatifard A. 2010. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLLchimeras, can link transcription elongation to leukemia. Mol Cell 37: 429-437.
129. Lindberg EH. 2005. Strategies for biology- and molecular-based treatment of myelodysplastic syndromes. Curr Drug Targets 6: 713-725.
130. Lindqvist CM, Nordlund J, Ekman D, Johansson A, Moghadam BT, Raine A, Overnas E, Dahlberg J, Wahlberg P, Henriksson N, et al. 2015. The mutational landscape in pediatric acute lymphoblastic leukemia deciphered by whole genome sequencing. Hum Mutat 36: 118-128.
131. Liu J, Cao L, Chen J, Song S, Lee IH, Quijano C, Liu H, Keyvanfar K, Chen H, Cao LY, et al. 2009. Bmi1 regulates mitochondrial function and theDNAdamage response pathway. Nature 459: 387-392.
132. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, Cruz-Gordillo P, Knoechel B, Asmann YW, Slager SL, et al. 2012. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci 109: 3879-3884.
133. Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR. 2003. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t (10;11)(q22;q23). Leukemia 17: 637-641.
134. Lux CT, Yoshimoto M, McGrath K, Conway SJ, Palis J, Yoder MC. 2008. All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood 111: 3435-3438.
135. Majewski IJ, Blewitt ME, de Graaf CA, McManus EJ, Bahlo M, Hilton AA, Hyland CD, Smyth GK, Corbin JE, Metcalf D, et al. 2008. Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol 6: e93.
136. Majewski IJ, Ritchie ME, Phipson B, Corbin J, Pakusch M, Ebert A, Busslinger M, Koseki H, Hu Y, Smyth GK, et al. 2010. Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood 116: 731-739.
137. Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD, Etchin J, Lawton L, Sallan SE, Silverman LB, et al. 2014. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346: 1373-1377.
138. Mar BG, Bullinger L, Basu E, Schlis K, Silverman LB, Dohner K, Armstrong SA. 2012. Sequencing histone-modifying enzymes identifies UTX mutations in acute lymphoblastic leukemia. Leukemia 26: 1881-1883.
139. Margueron R, Reinberg D. 2011. The Polycomb complex PRC2 and its mark in life. Nature 469: 343-349.
140. Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, Dynlacht BD, Reinberg D. 2008. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell 32: 503-518.
141. Martinez AM, Schuettengruber B, Sakr S, Janic A, Gonzalez C, Cavalli G. 2009. Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling. Nat Genet 41: 1076-1082.
142. Martinez-Garcia E, Popovic R, Min DJ, Sweet SM, Thomas PM, Zamdborg L, Heffner A, Will C, Lamy L, Staudt LM, et al. 2011. TheMMSEThistone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 117: 211-220.
143. McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, Smitheman KN, Ott HM, Pappalardi MB, Allen KE, et al. 2012a. 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 109: 2989-2994.
144. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A III, Diaz E, et al. 2012b. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492: 108-112.
145. McMahon KA, HiewSY, Hadjur S, Veiga-Fernandes H, Menzel U, Price AJ, Kioussis D, Williams O, Brady HJ. 2007. Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 1: 338-345.
146. Medvinsky A, Rybtsov S, Taoudi S. 2011. Embryonic origin of the adult hematopoietic system: advances and questions. Development 138: 1017-1031.
147. Mihara K, Chowdhury M, Nakaju N, Hidani S, Ihara A, Hyodo H, Yasunaga S, Takihara Y, Kimura A. 2006. Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis. Blood 107: 305-308.
148. Miller T, Krogan NJ, Dover J, Erdjument-Bromage H, Tempst P, Johnston M, Greenblatt JF, Shilatifard A. 2001. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc Natl Acad Sci 98: 12902-12907.
149. Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL. 2002. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 10: 1107-1117.
150. Milne TA, Kim J, Wang GG, Stadler SC, Basrur V, Whitcomb SJ, Wang Z, Ruthenburg AJ, Elenitoba-Johnson KS, Roeder RG, et al. 2010. Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell 38: 853-863.
151. Min J, Zhang Y, Xu RM. 2003. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev 17: 1823-1828.
152. Mishra BP, Zaffuto KM, Artinger EL, Org T, Mikkola HK, Cheng C, Djabali M, Ernst P. 2014. The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis. Cell Rep 7: 1239-1247.
153. Mochizuki-Kashio M, Aoyama K, Sashida G, Oshima M, Tomioka T, Muto T, Wang C, Iwama A. 2015. Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. Blood 126: 1172-1183.
154. Mohan M, Herz HM, Takahashi YH, Lin C, Lai KC, Zhang Y, Washburn MP, Florens L, Shilatifard A. 2010a. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev 24: 574-589.
155. Mohan M, Lin C, Guest E, Shilatifard A. 2010b. Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis. Nat Rev Cancer 10: 721-728.
156. Mohan M, Herz HM, Smith ER, Zhang Y, Jackson J, Washburn MP, Florens L, Eissenberg JC, Shilatifard A. 2011. The COMPASS family of H3K4 methylases in Drosophila. Mol Cell Biol 31: 4310-4318.
157. Mohty M, Yong AS, Szydlo RM, Apperley JF, Melo JV. 2007. The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. Blood 110: 380-383.
158. Moore MA, Metcalf D. 1970. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol 18: 279-296.
159. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, et al. 2011. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20: 11-24.
160. Morgan MA, Shilatifard A. 2015. Chromatin signatures of cancer. Genes Dev 29: 238-249.
161. Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, et al. 2011. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476: 298-303.
162. Mrozek K. 2008. Cytogenetic, molecular genetic, and clinical characteristics of acutemyeloid leukemia with a complex karyotype. Semin Oncol 35: 365-377.
163. Muto T, Sashida G, Oshima M,Wendt GR, Mochizuki-Kashio M, Nagata Y, Sanada M, Miyagi S, Saraya A, Kamio A, et al. 2013. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J Exp Med 210: 2627-2639.
164. Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R, Dubois G, Mazo A, Croce CM, Canaani E. 2002. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell 10: 1119-1128.
165. Neff T, Armstrong SA. 2013. Recent progress toward epigenetic therapies: the example of mixed lineage leukemia. Blood 121: 4847-4853.
166. Neumann M, Vosberg S, Schlee C, Heesch S, Schwartz S, Gokbuget N, Hoelzer D, Graf A, Krebs S, Bartram I, et al. 2015. Mutational spectrum of adult T-ALL. Oncotarget 6: 2754-2766.
167. Nguyen AT, Taranova O, He J, Zhang Y. 2011. DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood 117: 6912-6922.
168. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER, van der Heijden A, Scheele TN, Vandenberghe P, de Witte T, et al. 2010. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 42: 665-667.
169. Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, Ferres-Marco D, da Ros V, Tang Z, Siegle J, et al. 2012. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med 18: 298-301.
170. Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, Loizou E, Holmfeldt L, Strikoudis A, King B, et al. 2014. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514: 513-517.
171. Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H. 2006. Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med 203: 2247-2253.
172. Oguro H, Yuan J, Ichikawa H, IkawaT,Yamazaki S, Kawamoto H, Nakauchi H, Iwama A. 2010. Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the polycomb protein Bmi1. Cell Stem Cell 6: 279-286.
173. Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, Su L, Xu G, Zhang Y. 2005. hDOT1L links histone methylation to leukemogenesis. Cell 121: 167-178.
174. Okano M, Xie S, Li E. 1998. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19: 219-220.
175. Okosun J, Bodor C,Wang J, Araf S, Yang CY, Pan C, Boller S, Cittaro D, Bozek M, Iqbal S, et al. 2014. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 46: 176-181.
176. Ono R, Taki T, TaketaniT, Taniwaki M, Kobayashi H, Hayashi Y. 2002. LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res 62: 4075-4080.
177. Orkin SH, Zon LI. 2008. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132: 631-644.
178. Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y, Zhao C, Jiang M, Hu D, Agirre X, Niesvizky I, et al. 2015. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat Med 21: 1199-1208.
179. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ, Clarke MF. 2003. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423: 302-305.
180. Park SS, Kim JS, Tessarollo L, Owens JD, Peng L, Han SS, Tae Chung S, Torrey TA, Cheung WC, Polakiewicz RD, et al. 2005. Insertion of c-Myc into Igh induces B-cell and plasmacell neoplasms in mice. Cancer Res 65: 1306-1315.
181. Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. 2004. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23: 4061-4071.
182. Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, Kasper LH, Lerach S, Tang H, Ma J, et al. 2011. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471: 189-195.
183. Pasqualucci L, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes AB, Ouillette P, TrifonovV, Rossi D, Tabbo F, et al. 2014. Genetics of follicular lymphoma transformation. Cell Rep 6: 130-140.
184. Patel A, Dharmarajan V, Cosgrove MS. 2008. Structure of WDR5 bound to mixed lineage leukemia protein-1 peptide. J Biol Chem 283: 32158-32161.
185. Patel A, Dharmarajan V, Vought VE, Cosgrove MS. 2009. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem 284: 24242-24256.
186. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, et al. 2012. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366: 1079-1089.
187. Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, et al. 2012. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44: 751-759.
188. Piunti A, Shilatifard A. 2016. Epigenetic balance of gene expression by Polycomb and COMPASS families. Science 352: aad9780.
189. Piunti A, Rossi A, Cerutti A, Albert M, Jammula S, Scelfo A, Cedrone L, Fragola G, Olsson L, Koseki H, et al. 2014. Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication. Nat Commun 5: 3649.
190. Popovic R, Martinez-Garcia E, Giannopoulou EG, Zhang Q, Zhang Q, Ezponda T, Shah MY, Zheng Y, Will CM, Small EC, et al. 2014. Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation. PLoS Genet 10: e1004566.
191. Qiao Q, Li Y, Chen Z, Wang M, Reinberg D, Xu RM. 2011. The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. J Biol Chem 286: 8361-8368.
192. Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I,Wagner-Ballon O, Do Cruzeiro M, Delhommeau F, Arnulf B, Stern MH, et al. 2011. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20: 25-38.
193. Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, Wysocka J. 2011. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470: 279-283.
194. Rosati R, La Starza R, Veronese A, Aventin A, Schwienbacher C, Vallespi T, Negrini M, Martelli MF, Mecucci C. 2002. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 99: 3857-3860.
195. Saeidi K. 2016. Myeloproliferative neoplasms: current molecular biology and genetics. Crit Rev Oncol Hematol 98: 375-389.
196. Santos MA, Faryabi RB, Ergen AV, Day AM, Malhowski A, Canela A, Onozawa M, Lee JE, Callen E, Gutierrez-Martinez P, et al. 2014. DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier. Nature 514: 107-111.
197. Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Muller J. 2010. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465: 243-247.
198. Schichman SA, Caligiuri MA, Gu Y, Strout MP, Canaani E, Bloomfield CD, Croce CM. 1994. ALL-1 partial duplication in acute leukemia. Proc Natl Acad Sci 91: 6236-6239.
199. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, Eden E, Yakhini Z, Ben-Shushan E, Reubinoff BE, et al. 2007. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39: 232-236.
200. Schoumacher M, Le Corre S, Houy A, Mulugeta E, Stern MH, Roman-Roman S, Margueron R. 2016. Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status. Nat Med 22: 577-578.
201. Schwartz YB, Kahn TG, Nix DA, Li XY, Bourgon R, Biggin M, Pirrotta V. 2006. Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nat Genet 38: 700-705.
202. Score J, Hidalgo-Curtis C, Jones AV, Winkelmann N, Skinner A, Ward D, Zoi K, Ernst T, Stegelmann F, Dohner K, et al. 2012. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Blood 119: 1208-1213.
203. Shi AB, Murai MJ, He SH, Lund G, Hartley T, Purohit T, Reddy G, Chruszcz M, Grembecka J, Cierpicki T. 2012. Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 120: 4461-4469.
204. Shih AH, Abdel-Wahab O, Patel JP, Levine RL. 2012. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 12: 599-612.
205. Shih AH, Jiang Y, Meydan C, Shank K, Pandey S, Barreyro L, Antony-Debre I, Viale A, Socci N, Sun Y, et al. 2015. Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell 27: 502-515.
206. Shilatifard A. 1998. Factors regulating the transcriptional elongation activity of RNA polymerase II. FASEB J 12: 1437-1446.
207. Shilatifard A. 2012. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem 81: 65-95.
208. Shilatifard A, Lane WS, Jackson KW, Conaway RC, Conaway JW. 1996. An RNA polymerase II elongation factor encoded by the human ELL gene. Science 271: 1873-1876.
209. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, Kennedy JA, Schimmer AD, SchuhAC, YeeKW, et al. 2014. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506: 328-333.
210. Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S, Boucher G, Chagnon P, Drouin S, Lambert R, et al. 2012. Akey role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 26: 651-656.
211. Slack JM. 2002. Conrad Hal Waddington: the last Renaissance biologist? Nat Rev Genet 3: 889-895.
212. Smith E, Shilatifard A. 2013. Transcriptional elongation checkpoint control in development and disease. Genes Dev 27: 1079-1088.
213. Smith E, Shilatifard A. 2014. Enhancer biology and enhanceropathies. Nat Struct Mol Biol 21: 210-219.
214. Smith ER, Lin C, Garrett AS, Thornton J, Mohaghegh N, Hu D, Jackson J, Saraf A, Swanson SK, Seidel C, et al. 2011. The little elongation complex regulates small nuclear RNA transcription. Mol Cell 44: 954-965.
215. Souroullas GP, Jeck WR, Parker JS, Simon JM, Liu JY, Paulk J, Xiong J, Clark KS, Fedoriw Y, Qi J, et al. 2016. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med 22: 632-640.
216. Stegelmann F, Bullinger L, Schlenk RF, Paschka P, Griesshammer M, Blersch C, Kuhn S, Schauer S, Dohner H, Dohner K. 2011. DNMT3A mutations in myeloproliferative neoplasms. Leukemia 25: 1217-1219.
217. Steidl U, Steidl C, Ebralidze A, Chapuy B, Han HJ, Will B, Rosenbauer F, Becker A, Wagner K, Koschmieder S, et al. 2007. A distal single nucleotide polymorphism alters longrange regulation of the PU.1 gene in acute myeloid leukemia. J Clin Invest 117: 2611-2620.
218. Stein R, GruenbaumY, Pollack Y, Razin A, Cedar H. 1982. Clonal inheritance of the pattern of DNA methylation in mouse cells. Proc Natl Acad Sci 79: 61-65.
219. Struhl G. 1981. A gene product required for correct initiation of segmental determination in Drosophila. Nature 293: 36-41.
220. Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT, Tarakhovsky A. 2003. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol 4: 124-131.
221. Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H. 2007. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J Exp Med 204: 715-722.
222. Tahiliani M, Koh KP, Shen Y, PastorWA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, et al. 2009. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324: 930-935.
223. Taketani T, Taki T, Nakamura H, Taniwaki M, Masuda J, Hayashi Y. 2009. NUP98-NSD3 fusion gene in radiation-associated myelodysplastic syndrome with t(8;11)(p11;p15) and expression pattern of NSD family genes. Cancer Genet Cytogenet 190: 108-112.
224. Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J, Bezstarosti K, Taylor S, Ura H, Koide H, et al. 2012. RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell 148: 664-678.
225. Tefferi A. 2011. Mutations galore in myeloproliferative neoplasms: would the real Spartacus please stand up? Leukemia 25: 1059-1063.
226. Tetsu O, Ishihara H, Kanno R, Kamiyasu M, Inoue H, Tokuhisa T, Taniguchi M, Kanno M. 1998. mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc/cdc25. Immunity 9: 439-448.
227. 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.
228. Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, Iwamura C, Hosokawa H, Koseki H, Tokoyoda K, Suzuki Y, et al. 2013. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4+ T helper type 1 and type 2 cells. Immunity 39: 819-832.
229. Turkmen S, Gillessen-Kaesbach G, Meinecke P, Albrecht B, Neumann LM, Hesse V, Palanduz S, Balg S, Majewski F, Fuchs S, et al. 2003. Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. Eur J Hum Genet 11: 858-865.
230. Valinluck V, Sowers LC. 2007. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res 67: 946-950.
231. van den Boom V, Rozenveld-Geugien M, Bonardi F, Malanga D, van Gosliga D, Heijink AM, Viglietto G, Morrone G, Fusetti F, Vellenga E, et al. 2013. Nonredundant and locus-specific gene repression functions of PRC1 paralog family members in human hematopoietic stem/progenitor cells. Blood 121: 2452-2461.
232. van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C, Edkins S, Hardy C, O’Meara S, Teague J, et al. 2009. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 41: 521-523.
233. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, et al. 2002. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419: 624-629.
234. Walter MJ, Ding L, Shen D, Shao J, Grillot M, McLellan M, Fulton R, Schmidt H, Kalicki-Veizer J, O’Laughlin M, et al. 2011. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25: 1153-1158.
235. Wang GG, Cai L, Pasillas MP, Kamps MP. 2007. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 9: 804-812.
236. Whitman SP, Liu S, Vukosavljevic T, Rush LJ, Yu L, Liu C, Klisovic MI, Maharry K, Guimond M, Strout MP, et al. 2005. The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. Blood 106: 345-352.
237. Woods BA, Levine RL. 2015. The role of mutations in epigenetic regulators inmyeloid malignancies. Immunol Rev 263: 22-35.
238. Xie H, Xu J, Hsu JH, Nguyen M, Fujiwara Y, Peng C, Orkin SH. 2014. Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell 14: 68-80.
239. Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL, Ueno T, Soda M, HamadaT, Haruta H, et al. 2010. Array-based genomic resequencing of human leukemia. Oncogene 29: 3723-3731.
240. Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD, Yamamoto M. 2014. A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell 25: 415-427.
241. Yang L, Rau R, Goodell MA. 2015. DNMT3A in haematological malignancies. Nat Rev Cancer 15: 152-165.
242. Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, Morin RD, Mungall AJ, Meissner B, Boyle M, et al. 2011. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117: 2451-2459.
243. Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero DJ, Kitabayashi I, Herr W, Cleary ML. 2004. Leukemia protooncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol 24: 5639-5649.
244. Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML. 2005. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123: 207-218.
245. Zeisig BB, Milne T, Garcia-Cuellar MP, Schreiner S, Martin ME, Fuchs U, Borkhardt A, Chanda SK, Walker J, Soden R, et al. 2004. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol Cell Biol 24: 617-628.
246. Zhang J, Ding L, Holmfeldt L,WuG, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, et al. 2012. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481: 157-163.
247. Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, Dunphy C, ChoiW, Au WY, Srivastava G, et al. 2013. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci 110: 1398-1403.
248. Zhang Y, Kinkel S, Maksimovic J, Bandala-Sanchez E, Tanzer MC, Naselli G, Zhang JG, Zhan Y, Lew AM, Silke J, et al. 2014. The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood 124: 737-749.
249. Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB, Bansal M, Vlasevska S,MoT, Tang H, Basso K, et al. 2015. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat Med 21: 1190-1198.