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Therapeutic targeting potential of chromatin-associated proteins in MLL-rearranged acute leukemia

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Abstract

Background

Acute leukemias (AL) with a Mixed Lineage Leukemia (MLL) gene rearrangement (MLLr) represent a group of leukemic entities conferring intermediate to adverse prognoses. Multiple chromatin-associated proteins have been shown to play essential roles during the genesis of MLLr AL. Some chromatin-associated proteins function as negative regulators of MLLr AL whereas others are required for leukemic initiation or maintenance - the latter group constituting potential therapeutic targets. Most of the identified proteins have been functionally analyzed using experimental models with human/murine normal cells transformed by MLL-AF9 or other MLL fusion products, which may recapitulate most but not all aspects of human AML, such as immune system interactions – features of which the importance is rapidly emerging.

Conclusions

Here, we review chromatin-associated proteins fundamental to MLLr AL development, highlighting those with targeting potential by small molecule inhibitors. In particular, we focus on synthetic targeting of multiple chromatin-associated proteins, a strategy that shows superior therapeutic efficacy and offers hope for overcoming drug resistance.

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References

  1. C. Röllig, M. Bornhäuser, C. Thiede, F. Taube, M. Kramer, B. Mohr, W. Aulitzky, H. Bodenstein, H.-J. Tischler, R. Stuhlmann, U. Schuler, F. Stölzel, M. von Bonin, H. Wandt, K. Schäfer-Eckart, M. Schaich, G. Ehninger, Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J. Clin. Oncol. 29, 2758–2765 (2011)

    Article  PubMed  Google Scholar 

  2. C.H. Pui, F.G. Behm, J.R. Downing, M.L. Hancock, S.A. Shurtleff, R.C. Ribeiro, D.R. Head, H.H. Mahmoud, J.T. Sandlund, W.L. Furman, 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. J. Clin. Oncol. 12, 909–915 (1994)

    Article  CAS  PubMed  Google Scholar 

  3. C. Meyer, T. Burmeister, D. Gröger, G. Tsaur, L. Fechina, A. Renneville, R. Sutton, N.C. Venn, M. Emerenciano, M.S. Pombo-de-Oliveira, C. Barbieri Blunck, B. Almeida Lopes, J. Zuna, J. Trka, P. Ballerini, H. Lapillonne, M. de Braekeleer, G. Cazzaniga, L. Corral Abascal, V.H.J. van der Velden, E. Delabesse, T.S. Park, S.H. Oh, M.L.M. Silva, T. Lund-Aho, V. Juvonen, A.S. Moore, O. Heidenreich, J. Vormoor, E. Zerkalenkova, Y. Olshanskaya, C. Bueno, P. Menendez, A. Teigler-Schlegel, U. Zur Stadt, J. Lentes, G. Göhring, A. Kustanovich, O. Aleinikova, B.W. Schäfer, S. Kubetzko, H.O. Madsen, B. Gruhn, X. Duarte, P. Gameiro, E. Lippert, A. Bidet, J.M. Cayuela, E. Clappier, C.N. Alonso, C.M. Zwaan, M.M. van den Heuvel-Eibrink, S. Izraeli, L. Trakhtenbrot, P. Archer, J. Hancock, A. Möricke, J. Alten, M. Schrappe, M. Stanulla, S. Strehl, A. Attarbaschi, M. Dworzak, O.A. Haas, R. Panzer-Grümayer, L. Sedék, T. Szczepański, A. Caye, L. Suarez, H. Cavé, R. Marschalek, The MLL recombinome of acute leukemias in 2017. Leukemia 32, 273–284 (2018)

    Article  CAS  PubMed  Google Scholar 

  4. A.V. Krivtsov, S.A. Armstrong, MLL translocations, histone modifications and leukaemia stem-cell development. Nat. Rev. Cancer 7, 823–833 (2007)

    Article  CAS  PubMed  Google Scholar 

  5. P.M. Ayton, M.L. Cleary, Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 17, 2298–2307 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Y. Wang, A.V. Krivtsov, A.U. Sinha, T.E. North, W. Goessling, Z. Feng, L.I. Zon, S.A. Armstrong, The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 327, 1650–1653 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. L. Zhu, Q. Li, S.H.K. Wong, M. Huang, B.J. Klein, J. Shen, L. Ikenouye, M. Onishi, D. Schneidawind, C. Buechele, L. Hansen, J. Duque-Afonso, F. Zhu, G.M. Martin, O. Gozani, R. Majeti, T.G. Kutateladze, M.L. Cleary, ASH1L links histone H3 lysine 36 dimethylation to MLL leukemia. Cancer Discov. 6, 770–783 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Y. Zheng, H. Zhang, Y. Wang, X. Li, P. Lu, F. Dong, Y. Pang, S. Ma, H. Cheng, S. Hao, F. Tang, W. Yuan, X. Zhang, T. Cheng, Loss of Dnmt3b accelerates MLL-AF9 leukemia progression. Leukemia 30, 2373–2384 (2016)

    Article  CAS  PubMed  Google Scholar 

  9. M.-J. Chang, H. Wu, N.J. Achille, M.R. Reisenauer, C.-W. Chou, N.J. Zeleznik-Le, C.S. Hemenway, W. Zhang, Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes. Cancer Res. 70, 10234–10242 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. K.M. Bernt, N. Zhu, A.U. Sinha, S. Vempati, J. Faber, A.V. Krivtsov, Z. Feng, N. Punt, A. Daigle, L. Bullinger, R.M. Pollock, V.M. Richon, A.L. Kung, S.A. Armstrong, MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. D.G. Valerio, H. Xu, M.E. Eisold, C.M. Woolthuis, T.K. Pandita, S.A. Armstrong, Histone acetyltransferase activity of MOF is required for adult but not early fetal hematopoiesis in mice. Blood 129, 48–59 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. T. Neff, A.U. Sinha, M.J. Kluk, N. Zhu, M.H. Khattab, L. Stein, H. Xie, S.H. Orkin, S.A. Armstrong, Polycomb repressive complex 2 is required for MLL-AF9 leukemia. Proc. Natl. Acad. Sci. U. S. A. 109, 5028–5033 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  13. B. Zhou, J. Wang, S.Y. Lee, J. Xiong, N. Bhanu, Q. Guo, P. Ma, Y. Sun, R.C. Rao, B.A. Garcia, J.L. Hess, Y. Dou, PRDM16 Suppresses MLL1r Leukemia via Intrinsic Histone Methyltransferase Activity. Mol. Cell 62, 222–236 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. N. Cheung, T.K. Fung, B.B. Zeisig, K. Holmes, J.K. Rane, K.A. Mowen, M.G. Finn, B. Lenhard, L.C. Chan, C.W.E. So, Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia. Cancer Cell 29, 32–48 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. S. Kaushik, F. Liu, K.J. Veazey, G. Gao, P. Das, L.F. Neves, K. Lin, Y. Zhong, Y. Lu, V. Giuliani, M.T. Bedford, S.D. Nimer, M.A. Santos, Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia 32, 499–509 (2018)

    Article  CAS  PubMed  Google Scholar 

  16. W.J. Harris, X. Huang, J.T. Lynch, G.J. Spencer, J.R. Hitchin, Y. Li, F. Ciceri, J.G. Blaser, B.F. Greystoke, A.M. Jordan, C.J. Miller, D.J. Ogilvie, T.C.P. Somervaille, The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473–487 (2012)

    Article  CAS  PubMed  Google Scholar 

  17. N. Zhu, M. Chen, R. Eng, J. DeJong, A.U. Sinha, N.F. Rahnamay, R. Koche, F. Al-Shahrour, J.C. Minehart, C.-W. Chen, A.J. Deshpande, H. Xu, S.H. Chu, B.L. Ebert, R.G. Roeder, S.A. Armstrong, MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J. Clin. Invest. 126, 997–1011 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  18. P. Sroczynska, V.A. Cruickshank, J.-P. Bukowski, S. Miyagi, F.O. Bagger, J. Walfridsson, M.B. Schuster, B. Porse, K. Helin, shRNA screening identifies JMJD1C as being required for leukemia maintenance. Blood 123, 1870–1882 (2014)

    Article  CAS  PubMed  Google Scholar 

  19. S.H.K. Wong, D.L. Goode, M. Iwasaki, M.C. Wei, H.-P. Kuo, L. Zhu, D. Schneidawind, J. Duque-Afonso, Z. Weng, M.L. Cleary, The H3K4-Methyl epigenome regulates leukemia stem cell oncogenic potential. Cancer Cell 28, 198–209 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. H. Huang, X. Jiang, Z. Li, Y. Li, C.-X. Song, C. He, M. Sun, P. Chen, S. Gurbuxani, J. Wang, G.-M. Hong, A.G. Elkahloun, S. Arnovitz, J. Wang, K. Szulwach, L. Lin, C. Street, M. Wunderlich, M. Dawlaty, M.B. Neilly, R. Jaenisch, F.-C. Yang, J.C. Mulloy, P. Jin, P.P. Liu, J.D. Rowley, M. Xu, C. He, J. Chen, TET1 plays an essential oncogenic role in MLL-rearranged leukemia. Proc. Natl. Acad. Sci. U. S. A. 110, 11994–11999 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  21. J. Zuber, J. Shi, E. Wang, A.R. Rappaport, H. Herrmann, E.A. Sison, D. Magoon, J. Qi, K. Blatt, M. Wunderlich, M.J. Taylor, C. Johns, A. Chicas, J.C. Mulloy, S.C. Kogan, P. Brown, P. Valent, J.E. Bradner, S.W. Lowe, C.R. Vakoc, RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. C.Y. Fong, O. Gilan, E.Y.N. Lam, A.F. Rubin, S. Ftouni, D. Tyler, K. Stanley, D. Sinha, P. Yeh, J. Morison, G. Giotopoulos, D. Lugo, P. Jeffrey, S.C.-W. Lee, C. Carpenter, R. Gregory, R.G. Ramsay, S.W. Lane, O. Abdel-Wahab, T. Kouzarides, R.W. Johnstone, S.-J. Dawson, B.J.P. Huntly, R.K. Prinjha, A.T. Papenfuss, M.A. Dawson, BET inhibitor resistance emerges from leukaemia stem cells. Nature 525, 538–542 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. J. Tan, M. Jones, H. Koseki, M. Nakayama, A.G. Muntean, I. Maillard, J.L. Hess, CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell 20, 563–575 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. A. Yokoyama, M.L. Cleary, Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell 14, 36–46 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. A. Yokoyama, T.C.P. Somervaille, K.S. Smith, O. Rozenblatt-Rosen, M. Meyerson, M.L. Cleary, The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123, 207–218 (2005)

    Article  CAS  PubMed  Google Scholar 

  26. E. Wang, S. Kawaoka, M. Yu, J. Shi, T. Ni, W. Yang, J. Zhu, R.G. Roeder, C.R. Vakoc, Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia. Proc. Natl. Acad. Sci. U. S. A. 110, 3901–3906 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  27. N. Rapin, B.T. Porse, Oncogenic fusion proteins expressed in immature hematopoietic cells fail to recapitulate the transcriptional changes observed in human AML. Oncogenesis 3, e106 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. G.D. Gregory, C.R. Vakoc, T. Rozovskaia, X. Zheng, S. Patel, T. Nakamura, E. Canaani, G.A. Blobel, Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Mol. Cell. Biol. 27, 8466–8479 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Y. Tanaka, Z.-I. Katagiri, K. Kawahashi, D. Kioussis, S. Kitajima, Trithorax-group protein ASH1 methylates histone H3 lysine 36. Gene 397, 161–168 (2007)

    Article  CAS  PubMed  Google Scholar 

  30. H. Miyazaki, K. Higashimoto, Y. Yada, T.A. Endo, J. Sharif, T. Komori, M. Matsuda, Y. Koseki, M. Nakayama, H. Soejima, H. Handa, H. Koseki, S. Hirose, K. Nishioka, Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract polycomb silencing. PLoS Genet. 9, e1003897 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. S. An, K.J. Yeo, Y.H. Jeon, J.-J. Song, Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism. J. Biol. Chem. 286, 8369–8374 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. M. Jones, J. Chase, M. Brinkmeier, J. Xu, D.N. Weinberg, J. Schira, A. Friedman, S. Malek, J. Grembecka, T. Cierpicki, Y. Dou, S.A. Camper, I. Maillard, Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells. J. Clin. Invest. 125, 2007–2020 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  33. M. Okano, D.W. Bell, D.A. Haber, E. Li, DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999)

    Article  CAS  PubMed  Google Scholar 

  34. S.-i. Mizuno, Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 97, 1172–1179 (2001)

    Article  CAS  PubMed  Google Scholar 

  35. D. Watanabe, I. Suetake, S. Tajima, K. Hanaoka, Expression of Dnmt3b in mouse hematopoietic progenitor cells and spermatogonia at specific stages. Gene Expr. Patterns 5, 43–49 (2004)

    Article  CAS  PubMed  Google Scholar 

  36. T.J. Ley, L. Ding, M.J. Walter, M.D. McLellan, T. Lamprecht, D.E. Larson, C. Kandoth, J.E. Payton, J. Baty, J. Welch, C.C. Harris, C.F. Lichti, R.R. Townsend, R.S. Fulton, D.J. Dooling, D.C. Koboldt, H. Schmidt, Q. Zhang, J.R. Osborne, L. Lin, M. O'Laughlin, J.F. McMichael, K.D. Delehaunty, S.D. McGrath, L.A. Fulton, V.J. Magrini, T.L. Vickery, J. Hundal, L.L. Cook, J.J. Conyers, G.W. Swift, J.P. Reed, P.A. Alldredge, T. Wylie, J. Walker, J. Kalicki, M.A. Watson, S. Heath, W.D. Shannon, N. Varghese, R. Nagarajan, P. Westervelt, M.H. Tomasson, D.C. Link, T.A. Graubert, J.F. DiPersio, E.R. Mardis, R.K. Wilson, DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. X.-J. Yan, J. Xu, Z.-H. Gu, C.-M. Pan, G. Lu, Y. Shen, J.-Y. Shi, Y.-M. Zhu, L. Tang, X.-W. Zhang, W.-X. Liang, J.-Q. Mi, H.-D. Song, K.-Q. Li, Z. Chen, S.-J. Chen, Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet. 43, 309–315 (2011)

    Article  CAS  PubMed  Google Scholar 

  38. M.J. Walter, L. Ding, D. Shen, J. Shao, M. Grillot, M. McLellan, R. Fulton, H. Schmidt, J. Kalicki-Veizer, M. O'Laughlin, C. Kandoth, J. Baty, P. Westervelt, J.F. DiPersio, E.R. Mardis, R.K. Wilson, T.J. Ley, T.A. Graubert, Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25, 1153–1158 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. L. Couronné, C. Bastard, O.A. Bernard, TET2 and DNMT3A mutations in human T-cell lymphoma. N. Engl. J. Med. 366, 95–96 (2012)

    Article  PubMed  Google Scholar 

  40. S. Hayette, X. Thomas, L. Jallades, K. Chabane, C. Charlot, I. Tigaud, S. Gazzo, S. Morisset, P. Cornillet-Lefebvre, A. Plesa, S. Huet, A. Renneville, G. Salles, F.E. Nicolini, J.-P. Magaud, M. Michallet, High DNA methyltransferase DNMT3B levels: a poor prognostic marker in acute myeloid leukemia. PLoS ONE 7, e51527 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. C. Niederwieser, J. Kohlschmidt, S. Volinia, S.P. Whitman, K.H. Metzeler, A.-K. Eisfeld, K. Maharry, P. Yan, D. Frankhouser, H. Becker, S. Schwind, A.J. Carroll, D. Nicolet, J.H. Mendler, J.P. Curfman, Y.-Z. Wu, M.R. Baer, B.L. Powell, J.E. Kolitz, J.O. Moore, T.H. Carter, R. Bundschuh, R.A. Larson, R.M. Stone, K. Mrózek, G. Marcucci, C.D. Bloomfield, Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia. Leukemia 29, 567–575 (2015)

    Article  CAS  PubMed  Google Scholar 

  42. I. Schulze, C. Rohde, M. Scheller-Wendorff, N. Bäumer, A. Krause, F. Herbst, P. Riemke, K. Hebestreit, P. Tschanter, Q. Lin, H. Linhart, L.A. Godley, H. Glimm, M. Dugas, W. Wagner, W.E. Berdel, F. Rosenbauer, C. Müller-Tidow, Increased DNA methylation of Dnmt3b targets impairs leukemogenesis. Blood 127, 1575–1586 (2016)

    Article  CAS  PubMed  Google Scholar 

  43. Q. Feng, H. Wang, H.H. Ng, H. Erdjument-Bromage, P. Tempst, K. Struhl, Y. Zhang, Methylation of H3-Lysine 79 Is Mediated by a New Family of HMTases without a SET Domain. Curr. Biol. 12, 1052–1058 (2002)

    Article  CAS  PubMed  Google Scholar 

  44. S.Y. Jo, E.M. Granowicz, I. Maillard, D. Thomas, J.L. Hess, Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood 117, 4759–4768 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. A.T. Nguyen, J. He, O. Taranova, Y. Zhang, Essential role of DOT1L in maintaining normal adult hematopoiesis. Cell Res. 21, 1370–1373 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. A.T. Nguyen, O. Taranova, J. He, Y. Zhang, DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood 117, 6912–6922 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Y. Okada, Q. Feng, Y. Lin, Q. Jiang, Y. Li, V.M. Coffield, L. Su, G. Xu, Y. Zhang, hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005)

    Article  CAS  PubMed  Google Scholar 

  48. D. Mueller, C. Bach, D. Zeisig, M.-P. Garcia-Cuellar, S. Monroe, A. Sreekumar, R. Zhou, A. Nesvizhskii, A. Chinnaiyan, J.L. Hess, R.K. Slany, A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 110, 4445–4454 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. E. Bitoun, P.L. Oliver, K.E. Davies, The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16, 92–106 (2007)

    Article  CAS  PubMed  Google Scholar 

  50. S.C. Monroe, S.Y. Jo, D.S. Sanders, V. Basrur, K.S. Elenitoba-Johnson, R.K. Slany, J.L. Hess, MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia. Exp. Hematol. 39, 77–86.e1-5 (2011)

    Article  CAS  PubMed  Google Scholar 

  51. M. Mohan, H.-M. Herz, Y.-H. Takahashi, C. Lin, K.C. Lai, Y. Zhang, M.P. Washburn, L. Florens, A. Shilatifard, Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 24, 574–589 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. A. Benedikt, S. Baltruschat, B. Scholz, A. Bursen, T.N. Arrey, B. Meyer, L. Varagnolo, A.M. Müller, M. Karas, T. Dingermann, R. Marschalek, The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures. Leukemia 25, 135–144 (2011)

    Article  CAS  PubMed  Google Scholar 

  53. S.R. Daigle, E.J. Olhava, C.A. Therkelsen, C.R. Majer, C.J. Sneeringer, J. Song, L.D. Johnston, M.P. Scott, J.J. Smith, Y. Xiao, L. Jin, K.W. Kuntz, R. Chesworth, M.P. Moyer, K.M. Bernt, J.-C. Tseng, A.L. Kung, S.A. Armstrong, R.A. Copeland, V.M. Richon, R.M. Pollock, Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53–65 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. S.R. Daigle, E.J. Olhava, C.A. Therkelsen, A. Basavapathruni, L. Jin, P.A. Boriack-Sjodin, C.J. Allain, C.R. Klaus, A. Raimondi, M.P. Scott, N.J. Waters, R. Chesworth, M.P. Moyer, R.A. Copeland, V.M. Richon, R.M. Pollock, Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122, 1017–1025 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. A.J. Deshpande, L. Chen, M. Fazio, A.U. Sinha, K.M. Bernt, D. Banka, S. Dias, J. Chang, E.J. Olhava, S.R. Daigle, V.M. Richon, R.M. Pollock, S.A. Armstrong, Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. Blood 121, 2533–2541 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. S.M. Sarkaria, M.J. Christopher, J.M. Klco, T.J. Ley, Primary acute myeloid leukemia cells with IDH1 or IDH2 mutations respond to a DOT1L inhibitor in vitro. Leukemia 28, 2403–2406 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. M.W.M. Kühn, M.J. Hadler, S.R. Daigle, R.P. Koche, A.V. Krivtsov, E.J. Olhava, M.A. Caligiuri, G. Huang, J.E. Bradner, R.M. Pollock, S.A. Armstrong, MLL partial tandem duplication leukemia cells are sensitive to small molecule DOT1L inhibition. Haematologica 100, e190–e193 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. A.J. Deshpande, A. Deshpande, A.U. Sinha, L. Chen, J. Chang, A. Cihan, M. Fazio, C.-W. Chen, N. Zhu, R. Koche, L. Dzhekieva, G. Ibáñez, S. Dias, D. Banka, A. Krivtsov, M. Luo, R.G. Roeder, J.E. Bradner, K.M. Bernt, S.A. Armstrong, AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell 26, 896–908 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. R.E. Rau, B.A. Rodriguez, M. Luo, M. Jeong, A. Rosen, J.H. Rogers, C.T. Campbell, S.R. Daigle, L. Deng, Y. Song, S. Sweet, T. Chevassut, M. Andreeff, S.M. Kornblau, W. Li, M.A. Goodell, DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia. Blood 128, 971–981 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. C.T. Campbell, J.N. Haladyna, D.A. Drubin, T.M. Thomson, M.J. Maria, T. Yamauchi, N.J. Waters, E.J. Olhava, R.M. Pollock, J.J. Smith, R.A. Copeland, S.J. Blakemore, K.M. Bernt, S.R. Daigle, Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia. Mol. Cancer Ther. 16, 1669–1679 (2017)

    Article  CAS  PubMed  Google Scholar 

  61. W. Liu, L. Deng, Y. Song, M. Redell, DOT1L inhibition sensitizes MLL-rearranged AML to chemotherapy. PLoS ONE 9, e98270 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. C.R. Klaus, D. Iwanowicz, D. Johnston, C.A. Campbell, J.J. Smith, M.P. Moyer, R.A. Copeland, E.J. Olhava, M.P. Scott, R.M. Pollock, S.R. Daigle, A. Raimondi, DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells. J. Pharmacol. Exp. Ther. 350, 646–656 (2014)

    Article  CAS  PubMed  Google Scholar 

  63. C.-W. Chen, R.P. Koche, A.U. Sinha, A.J. Deshpande, N. Zhu, R. Eng, J.G. Doench, H. Xu, S.H. Chu, J. Qi, X. Wang, C. Delaney, K.M. Bernt, D.E. Root, W.C. Hahn, J.E. Bradner, S.A. Armstrong, DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat. Med. 21, 335–343 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. A. Hilfiker, D. Hilfiker-Kleiner, A. Pannuti, J.C. Lucchesi, mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J. 16, 2054–2060 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. M. Taipale, S. Rea, K. Richter, A. Vilar, P. Lichter, A. Imhof, A. Akhtar, hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol. Cell. Biol. 25, 6798–6810 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. D.G. Valerio, H. Xu, C.-W. Chen, T. Hoshii, M.E. Eisold, C. Delaney, M. Cusan, A.J. Deshpande, C.-H. Huang, A. Lujambio, Y.G. Zheng, J. Zuber, T.K. Pandita, S.W. Lowe, S.A. Armstrong, Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis. Cancer Res. 77, 1753–1762 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Y. Dou, T.A. Milne, A.J. Tackett, E.R. Smith, A. Fukuda, J. Wysocka, C.D. Allis, B.T. Chait, J.L. Hess, R.G. Roeder, Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873–885 (2005)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. F.W. Schmitges, A.B. Prusty, M. Faty, A. Stützer, G.M. Lingaraju, J. Aiwazian, R. Sack, D. Hess, L. Li, S. Zhou, R.D. Bunker, U. Wirth, T. Bouwmeester, A. Bauer, N. Ly-Hartig, K. Zhao, H. Chan, J. Gu, H. Gut, W. Fischle, J. Müller, N.H. Thomä, Histone methylation by PRC2 is inhibited by active chromatin marks. Mol. Cell 42, 330–341 (2011)

    Article  CAS  PubMed  Google Scholar 

  70. I.J. Majewski, M.E. Blewitt, C.A. de Graaf, E.J. McManus, M. Bahlo, A.A. Hilton, C.D. Hyland, G.K. Smyth, J.E. Corbin, D. Metcalf, W.S. Alexander, D.J. Hilton, Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol. 6, e93 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. S.C.W. Lee, S. Miller, C. Hyland, M. Kauppi, M. Lebois, L. Di Rago, D. Metcalf, S.A. Kinkel, E.C. Josefsson, M.E. Blewitt, I.J. Majewski, W.S. Alexander, Polycomb repressive complex 2 component Suz12 is required for hematopoietic stem cell function and lymphopoiesis. Blood 126, 167–175 (2015)

    Article  CAS  PubMed  Google Scholar 

  72. W. Yu, F. Zhang, S. Wang, Y. Fu, J. Chen, X. Liang, H. Le, W.T. Pu, B. Zhang, Depletion of polycomb repressive complex 2 core component EED impairs fetal hematopoiesis. Cell Death Dis. 8, e2744 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. H. Xie, J. Xu, J.H. Hsu, M. Nguyen, Y. Fujiwara, C. Peng, S.H. Orkin, Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell 14, 68–80 (2014)

    Article  CAS  PubMed  Google Scholar 

  74. M. Mochizuki-Kashio, Y. Mishima, S. Miyagi, M. Negishi, A. Saraya, T. Konuma, J. Shinga, H. Koseki, A. Iwama, Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood 118, 6553–6561 (2011)

    Article  CAS  PubMed  Google Scholar 

  75. M. Mochizuki-Kashio, K. Aoyama, G. Sashida, M. Oshima, T. Tomioka, T. Muto, C. Wang, A. Iwama, Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. Blood 126, 1172–1183 (2015)

    Article  CAS  PubMed  Google Scholar 

  76. J. Shi, E. Wang, J. Zuber, A. Rappaport, M. Taylor, C. Johns, S.W. Lowe, C.R. Vakoc, 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)

    Article  CAS  PubMed  Google Scholar 

  77. W. Qi, K. Zhao, J. Gu, Y. Huang, Y. Wang, H. Zhang, M. Zhang, J. Zhang, Z. Yu, L. Li, L. Teng, S. Chuai, C. Zhang, M. Zhao, H. Chan, Z. Chen, D. Fang, Q. Fei, L. Feng, L. Feng, Y. Gao, H. Ge, X. Ge, G. Li, A. Lingel, Y. Lin, Y. Liu, F. Luo, M. Shi, L. Wang, Z. Wang, Y. Yu, J. Zeng, C. Zeng, L. Zhang, Q. Zhang, S. Zhou, C. Oyang, P. Atadja, E. Li, An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat. Chem. Biol. 13, 381–388 (2017)

    Article  CAS  PubMed  Google Scholar 

  78. Y. He, S. Selvaraju, M.L. Curtin, C.G. Jakob, H. Zhu, K.M. Comess, B. Shaw, J. The, E. Lima-Fernandes, M.M. Szewczyk, D. Cheng, K.L. Klinge, H.-Q. Li, M. Pliushchev, M.A. Algire, D. Maag, J. Guo, J. Dietrich, S.C. Panchal, A.M. Petros, R.F. Sweis, M. Torrent, L.J. Bigelow, G. Senisterra, F. Li, S. Kennedy, Q. Wu, D.J. Osterling, D.J. Lindley, W. Gao, S. Galasinski, D. Barsyte-Lovejoy, M. Vedadi, F.G. Buchanan, C.H. Arrowsmith, G.G. Chiang, C. Sun, W.N. Pappano, The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat. Chem. Biol. 13, 389–395 (2017)

    Article  CAS  PubMed  Google Scholar 

  79. B. Xu, D.M. On, A. Ma, T. Parton, K.D. Konze, S.G. Pattenden, D.F. Allison, L. Cai, S. Rockowitz, S. Liu, Y. Liu, F. Li, M. Vedadi, S.V. Frye, B.A. Garcia, D. Zheng, J. Jin, G.G. Wang, Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 125, 346–357 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. D. Honma, O. Kanno, J. Watanabe, J. Kinoshita, M. Hirasawa, E. Nosaka, M. Shiroishi, T. Takizawa, I. Yasumatsu, T. Horiuchi, A. Nakao, K. Suzuki, T. Yamasaki, K. Nakajima, M. Hayakawa, T. Yamazaki, A.S. Yadav, N. Adachi, Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 108, 2069–2078 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. I. Pinheiro, R. Margueron, N. Shukeir, M. Eisold, C. Fritzsch, F.M. Richter, G. Mittler, C. Genoud, S. Goyama, M. Kurokawa, J. Son, D. Reinberg, M. Lachner, T. Jenuwein, Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. Cell 150, 948–960 (2012)

    Article  CAS  PubMed  Google Scholar 

  82. F. Aguilo, S. Avagyan, A. Labar, A. Sevilla, D.-F. Lee, P. Kumar, I.R. Lemischka, B.Y. Zhou, H.-W. Snoeck, Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood 117, 5057–5066 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. E. Deneault, S. Cellot, A. Faubert, J.-P. Laverdure, M. Fréchette, J. Chagraoui, N. Mayotte, M. Sauvageau, S.B. Ting, G. Sauvageau, A functional screen to identify novel effectors of hematopoietic stem cell activity. Cell 137, 369–379 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. I. Nishikata, H. Sasaki, M. Iga, Y. Tateno, S. Imayoshi, N. Asou, T. Nakamura, K. Morishita, A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation. Blood 102, 3323–3332 (2003)

    Article  CAS  PubMed  Google Scholar 

  85. D.C. Shing, M. Trubia, F. Marchesi, E. Radaelli, E. Belloni, C. Tapinassi, E. Scanziani, C. Mecucci, B. Crescenzi, I. Lahortiga, M.D. Odero, G. Zardo, A. Gruszka, S. Minucci, P.P. Di Fiore, P.G. Pelicci, Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice. J. Clin. Invest. 117, 3696–3707 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  86. I. Sakai, T. Tamura, H. Narumi, N. Uchida, Y. Yakushijin, T. Hato, S. Fujita, M. Yasukawa, Novel RUNX1-PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22). Genes Chromosom. Cancer 44, 265–270 (2005)

    Article  CAS  PubMed  Google Scholar 

  87. C. Roche-Lestienne, L. Deluche, S. Corm, I. Tigaud, S. Joha, N. Philippe, S. Geffroy, J.-L. Laï, F.-E. Nicolini, C. Preudhomme, RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance. Blood 111, 3735–3741 (2008)

    Article  CAS  PubMed  Google Scholar 

  88. B.D. Strahl, S.D. Briggs, C.J. Brame, J.A. Caldwell, S.S. Koh, H. Ma, R.G. Cook, J. Shabanowitz, D.F. Hunt, M.R. Stallcup, C.D. Allis, Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1. Curr. Biol. 11, 996–1000 (2001)

    Article  CAS  PubMed  Google Scholar 

  89. T.L. Branscombe, A. Frankel, J.H. Lee, J.R. Cook, Z. Yang, S. Pestka, S. Clarke, PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins. J. Biol. Chem. 276, 32971–32976 (2001)

    Article  CAS  PubMed  Google Scholar 

  90. F. Liu, G. Cheng, P.-J. Hamard, S. Greenblatt, L. Wang, N. Man, F. Perna, H. Xu, M. Tadi, L. Luciani, S.D. Nimer, Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis. J. Clin. Invest. 125, 3532–3544 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  91. J. Serio, J. Ropa, W. Chen, M. Mysliwski, N. Saha, L. Chen, J. Wang, H. Miao, T. Cierpicki, J. Grembecka, A.G. Muntean, The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia. Oncogene 37, 450–460 (2018)

    Article  CAS  PubMed  Google Scholar 

  92. J.W. Edmunds, L.C. Mahadevan, A.L. Clayton, Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 27, 406–420 (2008)

    Article  CAS  PubMed  Google Scholar 

  93. Y.-L. Zhang, J.-W. Sun, Y.-Y. Xie, Y. Zhou, P. Liu, J.-C. Song, C.-H. Xu, L. Wang, D. Liu, A.-N. Xu, Z. Chen, S.-J. Chen, X.-J. Sun, Q.-H. Huang, Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Res. 28, 476–490 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. X. Zhu, F. He, H. Zeng, S. Ling, A. Chen, Y. Wang, X. Yan, W. Wei, Y. Pang, H. Cheng, C. Hua, Y. Zhang, X. Yang, X. Lu, L. Cao, L. Hao, L. Dong, W. Zou, J. Wu, X. Li, S. Zheng, J. Yan, J. Zhou, L. Zhang, S. Mi, X. Wang, L. Zhang, Y. Zou, Y. Chen, Z. Geng, J. Wang, J. Zhou, X. Liu, J. Wang, W. Yuan, G. Huang, T. Cheng, Q.-F. Wang, Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat. Genet. 46, 287–293 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Y. Shi, F. Lan, C. Matson, P. Mulligan, J.R. Whetstine, P.A. Cole, R.A. Casero, Y. Shi, Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004)

    Article  CAS  PubMed  Google Scholar 

  96. A. Sprüssel, J.H. Schulte, S. Weber, M. Necke, K. Händschke, T. Thor, K.W. Pajtler, A. Schramm, K. König, L. Diehl, P. Mestdagh, J. Vandesompele, F. Speleman, H. Jastrow, L.C. Heukamp, R. Schüle, U. Dührsen, R. Buettner, A. Eggert, J.R. Göthert, Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia 26, 2039–2051 (2012)

    Article  CAS  PubMed  Google Scholar 

  97. J.P. McGrath, K.E. Williamson, S. Balasubramanian, S. Odate, S. Arora, C. Hatton, T.M. Edwards, T. O'Brien, S. Magnuson, D. Stokoe, D.L. Daniels, B.M. Bryant, P. Trojer, Pharmacological inhibition of the histone lysine demethylase KDM1A suppresses the growth of multiple acute myeloid eukemia subtypes. Cancer Res. 76, 1975–1988 (2016)

    Article  CAS  PubMed  Google Scholar 

  98. Y.-i. Tsukada, J. Fang, H. Erdjument-Bromage, M.E. Warren, C.H. Borchers, P. Tempst, Y. Zhang, Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006)

    Article  CAS  PubMed  Google Scholar 

  99. M. Brauchle, Z. Yao, R. Arora, S. Thigale, I. Clay, B. Inverardi, J. Fletcher, P. Taslimi, M.G. Acker, B. Gerrits, J. Voshol, A. Bauer, D. Schübeler, T. Bouwmeester, H. Ruffner, Protein complex interactor analysis and differential activity of KDM3 subfamily members towards H3K9 methylation. PLoS ONE 8, e60549 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. M. Katoh, M. Katoh, Comparative integromics on JMJD1C gene encoding histone demethylase: Conserved POU5F1 binding site elucidating mechanism of JMJD1C expression in undifferentiated ES cells and diffuse-type gastric cancer. Int. J. Oncol. 31, 219–223 (2007)

    CAS  PubMed  Google Scholar 

  101. P.A.C. Cloos, J. Christensen, K. Agger, A. Maiolica, J. Rappsilber, T. Antal, K.H. Hansen, K. Helin, The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006)

    Article  CAS  PubMed  Google Scholar 

  102. D.J. Seward, G. Cubberley, S. Kim, M. Schonewald, L. Zhang, B. Tripet, D.L. Bentley, Demethylation of trimethylated histone H3 Lys4 in vivo by JARID1 JmjC proteins. Nat. Struct. Mol. Biol. 14, 240–242 (2007)

    Article  CAS  PubMed  Google Scholar 

  103. S. Cellot, K.J. Hope, J. Chagraoui, M. Sauvageau, É. Deneault, T. MacRae, N. Mayotte, B.T. Wilhelm, J.R. Landry, S.B. Ting, J. Krosl, K. Humphries, A. Thompson, G. Sauvageau, RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity. Blood 122, 1545–1555 (2013)

    Article  CAS  PubMed  Google Scholar 

  104. M.H. Stewart, M. Albert, P. Sroczynska, V.A. Cruickshank, Y. Guo, D.J. Rossi, K. Helin, T. Enver, The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal in mice. Blood 125, 2075–2078 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. R.B. Lorsbach, J. Moore, S. Mathew, S.C. Raimondi, S.T. Mukatira, J.R. Downing, 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 (2003)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. A.J. Stonestrom, S.C. Hsu, K.S. Jahn, P. Huang, C.A. Keller, B.M. Giardine, S. Kadauke, A.E. Campbell, P. Evans, R.C. Hardison, G.A. Blobel, Functions of BET proteins in erythroid gene expression. Blood 125, 2825–2834 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. R.M. Rodriguez, B. Suarez-Alvarez, R. Salvanés, C. Huidobro, E.G. Toraño, J.L. Garcia-Perez, C. Lopez-Larrea, A.F. Fernandez, C. Bueno, P. Menendez, M.F. Fraga, Role of BRD4 in hematopoietic differentiation of embryonic stem cells. Epigenetics 9, 566–578 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. M.A. Dawson, R.K. Prinjha, A. Dittmann, G. Giotopoulos, M. Bantscheff, W.-I. Chan, S.C. Robson, C.-w. Chung, C. Hopf, M.M. Savitski, C. Huthmacher, E. Gudgin, D. Lugo, S. Beinke, T.D. Chapman, E.J. Roberts, P.E. Soden, K.R. Auger, O. Mirguet, K. Doehner, R. Delwel, A.K. Burnett, P. Jeffrey, G. Drewes, K. Lee, B.J.P. Huntly, T. Kouzarides, Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. A. Chaidos, V. Caputo, A. Karadimitris, Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence. Ther Adv Hematol 6, 128–141 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. K. Klauke, V. Radulović, M. Broekhuis, E. Weersing, E. Zwart, S. Olthof, M. Ritsema, S. Bruggeman, X. Wu, K. Helin, L. Bystrykh, G. de Haan, Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat. Cell Biol. 15, 353–362 (2013)

    Article  CAS  PubMed  Google Scholar 

  112. E. Maethner, M.-P. Garcia-Cuellar, C. Breitinger, S. Takacova, V. Divoky, J.L. Hess, R.K. Slany, MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells. Cell Rep. 3, 1553–1566 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. C.S. Hemenway, A.C. de Erkenez, G.C. Gould, The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias. Oncogene 20, 3798–3805 (2001)

    Article  CAS  PubMed  Google Scholar 

  114. H. Méreau, J. de Rijck, K. Cermáková, A. Kutz, S. Juge, J. Demeulemeester, R. Gijsbers, F. Christ, Z. Debyser, J. Schwaller, Impairing MLL-fusion gene-mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75). Leukemia 27, 1245–1253 (2013)

    Article  CAS  PubMed  Google Scholar 

  115. K. Cermáková, P. Tesina, J. Demeulemeester, S. El Ashkar, H. Méreau, J. Schwaller, P. Rezáčová, V. Veverka, J. de Rijck, Validation and structural characterization of the LEDGF/p75-MLL interface as a new target for the treatment of MLL-dependent leukemia. Cancer Res. 74, 5139–5151 (2014)

    Article  CAS  PubMed  Google Scholar 

  116. M.J. Murai, J. Pollock, S. He, H. Miao, T. Purohit, A. Yokom, J.L. Hess, A.G. Muntean, J. Grembecka, T. Cierpicki, The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV. Blood 124, 3730–3737 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Y.-X. Chen, J. Yan, K. Keeshan, A.T. Tubbs, H. Wang, A. Silva, E.J. Brown, J.L. Hess, W.S. Pear, X. Hua, The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression. Proc. Natl. Acad. Sci. U. S. A. 103, 1018–1023 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. E. Novotny, S. Compton, P.P. Liu, F.S. Collins, S.C. Chandrasekharappa, In vitro hematopoietic differentiation of mouse embryonic stem cells requires the tumor suppressor menin and is mediated by Hoxa9. Mech. Dev. 126, 517–522 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. I. Maillard, Y.-X. Chen, A. Friedman, Y. Yang, A.T. Tubbs, O. Shestova, W.S. Pear, X. Hua, Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. Blood 113, 1661–1669 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. S. Jin, H. Zhao, Y. Yi, Y. Nakata, A. Kalota, A.M. Gewirtz, c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis. J. Clin. Invest. 120, 593–606 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. J. Grembecka, S. He, A. Shi, T. Purohit, A.G. Muntean, R.J. Sorenson, H.D. Showalter, M.J. Murai, A.M. Belcher, T. Hartley, J.L. Hess, T. Cierpicki, Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 8, 277–284 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. D. Borkin, S. He, H. Miao, K. Kempinska, J. Pollock, J. Chase, T. Purohit, B. Malik, T. Zhao, J. Wang, B. Wen, H. Zong, M. Jones, G. Danet-Desnoyers, M.L. Guzman, M. Talpaz, D.L. Bixby, D. Sun, J.L. Hess, A.G. Muntean, I. Maillard, T. Cierpicki, J. Grembecka, Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell 27, 589–602 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. S. He, B. Malik, D. Borkin, H. Miao, S. Shukla, K. Kempinska, T. Purohit, J. Wang, L. Chen, B. Parkin, S.N. Malek, G. Danet-Desnoyers, A.G. Muntean, T. Cierpicki, J. Grembecka, Menin-MLL inhibitors block oncogenic transformation by MLL-fusion proteins in a fusion partner-independent manner. Leukemia 30, 508–513 (2016)

    Article  CAS  PubMed  Google Scholar 

  124. E. Shema, I. Tirosh, Y. Aylon, J. Huang, C. Ye, N. Moskovits, N. Raver-Shapira, N. Minsky, J. Pirngruber, G. Tarcic, P. Hublarova, L. Moyal, M. Gana-Weisz, Y. Shiloh, Y. Yarden, S.A. Johnsen, B. Vojtesek, S.L. Berger, M. Oren, The histone H2B-specific ubiquitin ligase RNF20/hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression. Genes Dev. 22, 2664–2676 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. A.S. Advani, C-kit as a target in the treatment of acute myelogenous leukemia. Curr Hematol Rep 4, 51–58 (2005)

    CAS  PubMed  Google Scholar 

  126. P. Rathert, M. Roth, T. Neumann, F. Muerdter, J.-S. Roe, M. Muhar, S. Deswal, S. Cerny-Reiterer, B. Peter, J. Jude, T. Hoffmann, Ł.M. Boryń, E. Axelsson, N. Schweifer, U. Tontsch-Grunt, L.E. Dow, D. Gianni, M. Pearson, P. Valent, A. Stark, N. Kraut, C.R. Vakoc, J. Zuber, Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525, 543–547 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. O. Gilan, E.Y.N. Lam, I. Becher, D. Lugo, E. Cannizzaro, G. Joberty, A. Ward, M. Wiese, C.Y. Fong, S. Ftouni, D. Tyler, K. Stanley, L. MacPherson, C.-F. Weng, Y.-C. Chan, M. Ghisi, D. Smil, C. Carpenter, P. Brown, N. Garton, M.E. Blewitt, A.J. Bannister, T. Kouzarides, B.J.P. Huntly, R.W. Johnstone, G. Drewes, S.-J. Dawson, C.H. Arrowsmith, P. Grandi, R.K. Prinjha, M.A. Dawson, Functional interdependence of BRD4 and DOT1L in MLL leukemia. Nat. Struct. Mol. Biol. 23, 673–681 (2016)

    Article  CAS  PubMed  Google Scholar 

  128. H. Okuda, B. Stanojevic, A. Kanai, T. Kawamura, S. Takahashi, H. Matsui, A. Takaori-Kondo, A. Yokoyama, Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia. J. Clin. Invest. 127, 1918–1931 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  129. C. Dafflon, V.J. Craig, H. Méreau, J. Gräsel, B. Schacher Engstler, G. Hoffman, F. Nigsch, S. Gaulis, L. Barys, M. Ito, J. Aguadé-Gorgorió, B. Bornhauser, J.-P. Bourquin, A. Proske, C. Stork-Fux, M. Murakami, W.R. Sellers, F. Hofmann, J. Schwaller, R. Tiedt, Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia. Leukemia 31, 1269–1277 (2017)

    Article  CAS  PubMed  Google Scholar 

  130. M.W.M. Kühn, E. Song, Z. Feng, A. Sinha, C.-W. Chen, A.J. Deshpande, M. Cusan, N. Farnoud, A. Mupo, C. Grove, R. Koche, J.E. Bradner, E. de Stanchina, G.S. Vassiliou, T. Hoshii, S.A. Armstrong, Targeting Chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 6, 1166–1181 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. A.C. Winters, K.M. Bernt, MLL-rearranged leukemias-An update on science and clinical approaches. Front. Pediatr. 5, 4 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  132. S.X. Pfister, A. Ashworth, Marked for death: targeting epigenetic changes in cancer. Nat. Rev. Drug Discov. 16, 241–263 (2017)

    Article  CAS  PubMed  Google Scholar 

  133. A. Chavez-Gonzalez, B. Bakhshinejad, K. Pakravan, M.L. Guzman, S. Babashah, Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer. Cell. Oncol. 40, 1–20 (2017)

    Article  CAS  Google Scholar 

  134. I.A. Voutsadakis, Expression and function of immune ligand-receptor pairs in NK cells and cancer stem cells: therapeutic implications. Cell. Oncol. 41, 107–121 (2018)

    Article  CAS  Google Scholar 

  135. P. Gotwals, S. Cameron, D. Cipolletta, V. Cremasco, A. Crystal, B. Hewes, B. Mueller, S. Quaratino, C. Sabatos-Peyton, L. Petruzzelli, J.A. Engelman, G. Dranoff, Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat. Rev. Cancer 17, 286–301 (2017)

    Article  CAS  PubMed  Google Scholar 

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Funding

Xin Xu was funded by the National Natural Science Foundation of China (NSFC; grant # 81370628 and # 81570157), the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry, Shandong Provincial Natural Science Foundation, China (grant # ZR2015CL023), and the Shandong Province Higher Educational Science and Technology Program (J16LL54).

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Xu, X., Schneider, B. Therapeutic targeting potential of chromatin-associated proteins in MLL-rearranged acute leukemia. Cell Oncol. 42, 117–130 (2019). https://doi.org/10.1007/s13402-018-0414-4

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