Investigation for a novel therapeutic target in acute myeloid leukemia with monosomy 7

1. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, Van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O'Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Döhner K, Schlenk RF, Döhner H, Campbell PJ. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 374(23), 2209-21 (2016).

2. Conway O'Brien E, Prideaux S, Chevassut T. The epigenetic landscape of acute myeloid leukemia. Adv Hematol. 2014, 103175 (2014).

3. Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood. 121(18), 3563-72 (2013).

4. Itzykson R, Fenaux P. Epigenetics of myelodysplastic syndromes. Leukemia. 28(3), 497-506 (2014).

5. Itzykson R, Kosmider O, Fenaux P. Somatic mutations and epigenetic abnormalities in myelodysplastic syndromes. Best Pract Res Clin Haematol. 26(4), 355-64 (2013).

6. Slovak ML1, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 96(13), 4075-83 (2000).

7. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 120(12), 2454-65 (2012).

8. Inaba T, Honda H, Matsui H. The enigma of monosomy 7. Blood. 131(26), 2891- 8 (2018).

9. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 298(5595), 1039-43 (2002).

10. Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 111(2), 185-96 (2002).

11. Müller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B, Miller EL, O'Connor MB, Kingston RE, Simon JA. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 111(2), 197-208 (2002).

12. Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol. 10(10), 697-708 (2009).

13. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 469(7330), 343-9 (2011).

14. Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, Sanada M, Miyagi S, Saraya A, Kamio A, Nagae G, Nakaseko C, Yokote K, Shimoda K, Koseki H, Suzuki Y, Sugano S, Aburatani H, Ogawa S, Iwama A. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J Exp Med. 210(12), 2627-39 (2013).

15. Sashida G, Harada H, Matsui H, Oshima M, Yui M, Harada Y, Tanaka S, Mochizuki-Kashio M, Wang C, Saraya A, Muto T, Hayashi Y, Suzuki K, Nakajima H, Inaba T, Koseki H, Huang G, Kitamura T, Iwama A. Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nat Commun. 5, 4177 (2014).

16. Ansari KI, Mandal SS. Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J. 277(8), 1790-804 (2010).

17. Herz HM, Hu D, Shilatifard A. Enhancer malfunction in cancer. Mol Cell. 53(6), 859-66 (2014).

18. Kühn MW, Radtke I, Bullinger L, Goorha S, Cheng J, Edelmann J, Gohlke J, Su X, Paschka P, Pounds S, Krauter J, Ganser A, Quessar A, Ribeiro R, Gaidzik VI, Shurtleff S, Krönke J, Holzmann K, Ma J, Schlenk RF, Rubnitz JE, Döhner K, Döhner H, Downing JR. High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations. Blood. 119(10), e67-75 (2012).

19. Dolnik A, Engelmann JC, Scharfenberger-Schmeer M, Mauch J, Kelkenberg- Schade S, Haldemann B, Fries T, Krönke J, Kühn MW, Paschka P, Kayser S, Wolf S, Gaidzik VI, Schlenk RF, Rücker FG, Döhner H, Lottaz C, Döhner K, Bullinger L. Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing. Blood. 120(18), e83-92 (2012).

20. Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, Shroff AS, Dickins RA, Vakoc CR, Bradner JE, Stock W, LeBeau MM, Shannon KM, Kogan S, Zuber J, Lowe SW. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell. 25(5), 652-65 (2014).

21. Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH. Integrating genetic approaches into the discovery of anticancer drugs. Science. 278(5340), 1064-8 (1997).

22. Chan DA1, Giaccia AJ. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat Rev Drug Discov. 10(5), 351-64 (2011).

23. O'Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer. Nat Rev Genet. 18(10), 613-23 (2017).

24. Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, Mizukami T, Shimada Y, Isomura H, Komachi M, Furuta K, Watanabe S, Nakano T, Yokota J, Kohno T. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 73(17), 5508- 18 (2013).

25. Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, Schultz DC, Liu Q, Shih IeM, Conejo-Garcia JR, Speicher DW, Zhang R. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 21(3), 231-8 (2015).

26. Ogiwara H, Sasaki M, Mitachi T, Oike T, Higuchi S, Tominaga Y, Kohno T. Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression. Cancer Discov. 6(4), 430-45 (2016).

27. Zhao D, Lu X, Wang G, Lan Z, Liao W, Li J, Liang X, Chen JR, Shah S, Shang X, Tang M, Deng P, Dey P, Chakravarti D, Chen P, Spring DJ, Navone NM, Troncoso P, Zhang J, Wang YA, DePinho RA. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature. 542(7642), 484-88 (2017).

28. Viswanathan SR, Nogueira MF, Buss CG, Krill-Burger JM, Wawer MJ, Malolepsza E, Berger AC, Choi PS, Shih J, Taylor AM, Tanenbaum B, Pedamallu CS, Cherniack AD, Tamayo P, Strathdee CA, Lage K, Carr SA, Schenone M, Bhatia SN, Vazquez F, Tsherniak A, Hahn WC, Meyerson M. Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer. Nat Genet. 50(7), 937-43 (2018).

29. Eisfeld AK, Kohlschmidt J, Mrózek K, Volinia S, Blachly JS, Nicolet D, Oakes C, Kroll K, Orwick S, Carroll AJ, Stone RM, Byrd JC, de la Chapelle A, Bloomfield CD. Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res. 77(1), 207-18 (2017).

30. He Y, Selvaraju S, Curtin ML, Jakob CG, Zhu H, Comess KM, Shaw B, The J, Lima-Fernandes E, Szewczyk MM, Cheng D, Klinge KL, Li HQ, Pliushchev M, Algire MA, Maag D, Guo J, Dietrich J, Panchal SC, Petros AM, Sweis RF, Torrent M, Bigelow LJ, Senisterra G, Li F, Kennedy S, Wu Q, Osterling DJ, Lindley DJ, Gao W, Galasinski S, Barsyte-Lovejoy D, Vedadi M, Buchanan FG, Arrowsmith CH, Chiang GG, Sun C, Pappano WN. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol. 13(4), 389-95 (2017).

31. Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, Cao L, Baiazitov R, Du W, Sydorenko N, Moon YC, Gibson L, Wang Y, Leung C, Iscove NN, Arrowsmith CH, Szentgyorgyi E, Gallinger S, Dick JE, O'Brien CA. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 20(1), 29-36 (2014).

32. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 48, 452-8 (2013).

33. Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ 3rd, Voigt P, Martin SR, Taylor WR, De Marco V, Pirrotta V, Reinberg D, Gamblin SJ. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature. 461(7265), 762-7 (200).

34. Montgomery ND, Yee D, Montgomery SA, Magnuson T. Molecular and functional mapping of EED motifs required for PRC2-dependent histone methylation. J Mol Biol. 374(5), 1145-57 (2007).

35. Cao Q, Wang X, Zhao M, Yang R, Malik R, Qiao Y, Poliakov A, Yocum AK, Li Y, Chen W, Cao X, Jiang X, Dahiya A, Harris C, Feng FY, Kalantry S, Qin ZS, Dhanasekaran SM, Chinnaiyan AM. The central role of EED in the orchestration of polycomb group complexes. Nat Commun. 5, 3127 (2014).

36. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 335, 440-2 (1988).

37. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9(1), 47-59 (2008).

38. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, Asplund A, Sjöstedt E, Lundberg E, Szigyarto CA, Skogs M, Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM, Lindskog C, Danielsson F, Mardinoglu A, Sivertsson A, von Feilitzen K, Forsberg M, Zwahlen M, Olsson I, Navani S, Huss M, Nielsen J, Ponten F, Uhlén M. Analysis of the human tissue-specific expression by genome- wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 13 (2), 397-406 (2014).

39. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 478, 524–8 (2011).

40. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 146, 904- 17 (2011).

41. Herrmann H, Blatt K, Shi J, Gleixner KV, Cerny-Reiterer S, Müllauer L, Vakoc CR, Sperr WR, Horny HP, Bradner JE, Zuber J, Valent P. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML. Oncotarget. 3, 1588-99 (2011).

42. Stewart HJ, Horne GA, Bastow S, Chevassut TJ. BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1. Cancer Med. 2, 826-35 (2012).

43. Fiskus W, Sharma S, Qi J, Valenta JA, Schaub LJ, Shah B, Peth K, Portier BP, Rodriguez M, Devaraj SG, Zhan M, Sheng J, Iyer SP, Bradner JE, Bhalla KN. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 13, 1142-54 (2014).

44. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Roberts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJ, Kouzarides T. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 478, 529-33 (2011).

45. Sebastian S, Sreenivas P, Sambasivan R, Cheedipudi S, Kandalla P, Pavlath GK, Dhawan J. MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation. Proc Natl Acad Sci U S A. 106(12), 4719-24 (2009).

46. Zhang X, Novera W, Zhang Y, Deng LW. MLL5 (KMT2E): structure, function, and clinical relevance. Cell Mol Life Sci. 74(13), 2333-44 (2017).

47. Petrini I, Meltzer PS, Kim IK, Lucchi M, Park KS, Fontanini G, Gao J, Zucali PA, Calabrese F, Favaretto A, Rea F, Rodriguez-Canales J, Walker RL, Pineda M, Zhu YJ, Lau C, Killian KJ, Bilke S, Voeller D, Dakshanamurthy S, Wang Y, Giaccone G. A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nat Genet. 46(8), 844-9 (2014).

48. MT Hemann, SW Lowe. The p53–Bcl-2 connection. Cell Death Differ. 13(8), 1256-9 (2006).

49. Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, Yuan GC, Orkin SH. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell. 32(4), 491- 502 (2008).

50. Sashida G, Wang C, Tomioka T, Oshima M, Aoyama K, Kanai A, Mochizuki- Kashio M, Harada H, Shimoda K, Iwama A. The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. J Exp Med. 213(8), 1459-77 (2016).

51. Ott CJ, Kopp N, Bird L, Paranal RM, Qi J, Bowman T, Rodig SJ, Kung AL, Bradner JE, Weinstock DM. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 120(14), 2843-52 (2012).

52. Seo HR, Kim J, Bae S, Soh JW, Lee YS. Cdk5-mediated phosphorylation of c- Myc on Ser-62 is essential in transcriptional activation of cyclin B1 by cyclin G1. J Biol Chem. 283(23), 15601-10 (2008).

53. Jin X, Fang R, Fan P, Zeng L, Zhang B, Lu X, Liu T. PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer. J Exp Clin Cancer Res. 38(1), 463 (2019).