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MOLECULAR TARGETS FOR THERAPY

Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2

Leukemia volume 36, pages 1048–1057 (2022)Cite this article

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Abstract

Activating mutations in EZH2, the catalytic component of PRC2, promote cell proliferation, tumorigenesis, and metastasis through enzymatic or non-enzymatic activity. The EZH2-Y641 gain-of-function mutation is one of the most significant in diffuse large B-cell lymphoma (DLBCL). Although EZH2 kinase inhibitors, such as EPZ-6438, provide clinical benefit, certain cancer cells are resistant to the enzymatic inhibition of EZH2 because of the inability to functionally target mutant EZH2, or because of cells’ dependence on the non-histone methyltransferase activity of EZH2. Consequently, destroying mutant EZH2 protein may be more effective in targeting EZH2 mutant cancers that are dependent on the non-catalytic activity of EZH2. Here, using extensive selectivity profiling, combined with genetic and animal model studies, we identified USP47 as a novel regulator of mutant EZH2. Inhibition of USP47 would be anticipated to block the function of mutated EZH2 through induction of EZH2 degradation by promoting its ubiquitination. Moreover, targeting of USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo. Taken together, we propose targeting USP47 with a small molecule inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression.

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Fig. 1: P22077 and 1247825-37-1, identified in a chemical screen, selectively inhibit proliferation of mutant EZH2-expressing leukemia and lymphoma cells.
Fig. 2: P22077 or 1247825-37-1 treatment leads to selective degradation of mutant EZH2 versus wt EZH2.
Fig. 3: P22077 promotes ubiquitin-mediated proteasomal degradation of mutant EZH2 and shortens protein half-life.
Fig. 4: Identification of USP47 as a stabilizing DUB for mutant EZH2.
Fig. 5: USP47 selectively targets mutant EZH2 versus wt EZH2.
Fig. 6: USP47 is highly expressed in mutant EZH2 cell lines and physically and selectively associates with mutant EZH2 versus wt EZH2.
Fig. 7: Targeting of USP47 leads to killing of EZH2-Y641N-positive cells in vivo.

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References

  1. 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. 2002;111:185–96.

    Article  CAS  PubMed  Google Scholar 

  2. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469:343–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu X, Wu Q, Li L. Functional and therapeutic significance of EZH2 in urological cancers. Oncotarget. 2017;8:38044–55.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22:128–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lunning MA, Green MR. Mutation of chromatin modifiers; an emerging hallmark of germinal center B-cell lymphomas. Blood cancer J. 2015;5:e361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–9.

    Article  CAS  PubMed  Google Scholar 

  7. Sashida G, Iwama A. Multifaceted role of the polycomb-group gene EZH2 in hematological malignancies. Int J Hematol. 2017;105:23–30.

    Article  CAS  PubMed  Google Scholar 

  8. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12.

    Article  CAS  PubMed  Google Scholar 

  9. Stasik S, Middeke JM, Kramer M, Röllig C, Krämer A, Scholl S, et al. EZH2 mutations and impact on clinical outcome: an analysis in 1,604 patients with newly diagnosed acute myeloid leukemia. Haematologica. 2020;105:e228–e231.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mechaal A, Menif S, Abbes S, Safra I. EZH2, new diagnosis and prognosis marker in acute myeloid leukemia patients. Adv Med Sci. 2019;64:395–401.

    Article  PubMed  Google Scholar 

  11. Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim KH, Kim W, Howard TP, Vazquez F, Tsherniak A, Wu JN, et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med. 2015;21:1491–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu S, Fatkhutdinov N, Fukumoto T, Bitler BG, Park PH, Kossenkov AV, et al. SWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells. Nat Commun. 2018;9:4116.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–4.

    Article  PubMed  Google Scholar 

  15. Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell. 2007;128:735–45.

    Article  CAS  PubMed  Google Scholar 

  16. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–43.

    Article  CAS  PubMed  Google Scholar 

  17. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dubois S, Mareschal S, Picquenot J-M, Viailly P-J, Bohers E, Cornic M, et al. Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: Implications for targeted EZH2 inhibitor therapy? Oncotarget. 2015;6:16712–24.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  20. Batra R, Kaur H, Jindal S. Extranodal large B-cell type aggressive non-Hodgkin’s lymphoma. Indian J Dent. 2014;5:225–8.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Fan L, Li L, Zhou Y, Li J. Rituximab-based therapy in newly diagnosed diffuse large B-Cell Lymphoma patients: Individualized risk-adapted therapy approach using molecular subtypes. J Hematol. 2017;6:33–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Held G, Pöschel V, Pfreundschuh M. Rituximab for the treatment of diffuse large B-cell lymphomas. Expert Rev anticancer Ther. 2006;6:1175–86.

    Article  CAS  PubMed  Google Scholar 

  23. Bödör C, O’Riain C, Wrench D, Matthews J, Iyengar S, Tayyib H, et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia. 2011;25:726–9.

    Article  PubMed  Google Scholar 

  24. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci USA. 2010;107:20980–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117:2451–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Venney D, Mohd-Sarip A, Mills KI. The impact of epigenetic modifications in myeloid malignancies. Int J Mol Sci. 2021; 9: 22.

  27. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tönnissen ER, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665–7.

    Article  CAS  PubMed  Google Scholar 

  28. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, et al. Clinical effect of point mutations in myelodysplastic syndromes. N. Engl J Med. 2011;364:2496–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23:677–92.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Therapeutics. 2014;13:842–54.

    Article  CAS  Google Scholar 

  31. Italiano A. Targeting epigenetics in sarcomas through EZH2 inhibition. J Hematol Oncol. 2020;13:33–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kurmasheva RT, Sammons M, Favours E, Wu J, Kurmashev D, Cosmopoulos K, et al. Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2017; 64: https://doi.org/10.1002/pbc.26218.

  33. Huang S, Wang Z, Zhou J, Huang J, Zhou L, Luo J, et al. EZH2 inhibitor GSK126 suppresses antitumor immunity by driving production of myeloid-derived suppressor cells. Cancer Res. 2019;79:2009.

    Article  CAS  PubMed  Google Scholar 

  34. Yap TA, Winter JN, Giulino-Roth L, Longley J, Lopez J, Michot JM, et al. Phase I study of the novel enhancer of zeste homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors. Clin Cancer Res. 2019;25:7331–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee ST, Li Z, Wu Z, Aau M, Guan P, Karuturi RK, et al. Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol cell. 2011;43:798–810.

    Article  CAS  PubMed  Google Scholar 

  36. Gibaja V, Shen F, Harari J, Korn J, Ruddy D, Saenz-Vash V, et al. Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors. Oncogene. 2016;35:558–66.

    Article  CAS  PubMed  Google Scholar 

  37. Li Z, Hou P, Fan D, Dong M, Ma M, Li H, et al. The degradation of EZH2 mediated by lncRNA ANCR attenuated the invasion and metastasis of breast cancer. Cell Death Differ. 2017;24:59–71.

    Article  PubMed  Google Scholar 

  38. Zhang P, Xiao Z, Wang S, Zhang M, Wei Y, Hang Q, et al. ZRANB1 Is an EZH2 deubiquitinase and a potential therapeutic target in breast cancer. Cell Rep. 2018;23:823–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wilkinson KD. Ubiquitination and deubiquitination: Targeting of proteins for degradation by the proteasome. Seminars Cell Developmental Biol. 2000;11: 141–8.

  40. D’Arcy P, Wang X, Linder S. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharm Ther. 2015;147:32–54.

    Article  Google Scholar 

  41. Fraile JM, Quesada V, Rodriguez D, Freije JM, Lopez-Otin C. Deubiquitinases in cancer: new functions and therapeutic options. Oncogene. 2012;31:2373–88.

    Article  CAS  PubMed  Google Scholar 

  42. Park JM, Lee JE, Park CM, Kim JH. USP44 promotes the tumorigenesis of prostate cancer cells through EZH2 protein stabilization. Mol Cells. 2019;42:17–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen Y, Zhou B, Chen D. USP21 promotes cell proliferation and metastasis through suppressing EZH2 ubiquitination in bladder carcinoma. Onco Targets Ther. 2017;10:681–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zheng N, Chu M, Lin M, He Y, Wang Z. USP7 stabilizes EZH2 and enhances cancer malignant progression. Am J Cancer Res. 2020;10:299–313.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wigle TJ, Knutson SK, Jin L, Kuntz KW, Pollock RM, Richon VM, et al. The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states. FEBS Lett. 2011;585:3011–4.

    Article  CAS  PubMed  Google Scholar 

  46. Messingerova L, Imrichova D, Kavcova H, Turakova K, Breier A, Sulova Z. Acute myeloid leukemia cells MOLM-13 and SKM-1 established for resistance by azacytidine are crossresistant to P-glycoprotein substrates. Toxicol Vitr. 2015;29:1405–15.

    Article  CAS  Google Scholar 

  47. Lei H, Xu H-Z, Shan H-Z, Liu M, Lu Y, Fang Z-X, et al. Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia. Nature. Communications. 2021;12:51.

    CAS  Google Scholar 

  48. Yang J, Weisberg EL, Liu X, Magin RS, Chan WC, Hu B, et al. Small molecule inhibition of deubiquitinating enzyme JOSD1 as a novel targeted therapy for leukemias with mutant JAK2. Leukemia 2021. [Online ahead of print].

  49. Bisserier M, Wajapeyee N. Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas. Blood. 2018;131:2125–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang Q, Han Q, Zi J, Ma J, Song H, Tian Y, et al. Mutations in EZH2 are associated with poor prognosis for patients with myeloid neoplasms.Genes Dis. 2019;6:276–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kasinath V, Faini M, Poepsel S, Reif D, Feng XA, Stjepanovic G, et al. Structures of human PRC2 with its cofactors AEBP2 and JARID2. Science. 2018;359:940–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jiao L, Liu X. Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science. 2015;350:aac4383.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Højfeldt JW, Laugesen A, Willumsen BM, Damhofer H, Hedehus L, Tvardovskiy A, et al. Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2. Nat Struct Mol Biol. 2018;25:225–32.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Yamaguchi H, Hung MC. Regulation and role of EZH2 in cancer. Cancer Res Treat. 2014;46:209–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhou J, Huang S, Wang Z, Huang J, Xu L, Tang X, et al. Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation. Nat Commun. 2019;10:2427.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol. 2020;13:104.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Zee BM, Levin RS, Xu B, LeRoy G, Wingreen NS, Garcia BA. In vivo residue-specific histone methylation dynamics. J Biol Chem. 2010;285:3341–50.

    Article  CAS  PubMed  Google Scholar 

  58. Waterborg JH. Dynamic methylation of alfalfa histone H3. J Biol Chem. 1993;268:4918–21.

    Article  CAS  PubMed  Google Scholar 

  59. Altun M, Kramer Holger B, Willems Lianne I, McDermott Jeffrey L, Leach Craig A, Goldenberg Seth J, et al. Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chem Biol. 2011;18:1401–12.

    Article  CAS  PubMed  Google Scholar 

  60. Weinstock J, Wu J, Cao P, Kingsbury WD, McDermott JL, Kodrasov MP, et al. Selective dual inhibitors of the cancer-related deubiquitylating proteases USP7 and USP47. ACS medicinal Chem Lett. 2012;3:789–92.

    Article  CAS  Google Scholar 

  61. Schauer NJ, Liu X, Magin RS, Doherty LM, Chan WC, Ficarro SB, et al. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Sci Rep. 2020;10:5324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang X, Cao W, Zhang J, Yan M, Xu Q, Wu X, et al. A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination. Embo J. 2017;36:1243–60.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Yang SW, Oh KH, Park E, Chang HM, Park JM, Seong MW, et al. USP47 and C Terminus of Hsp70-Interacting Protein (CHIP) antagonistically regulate Katanin-p60-mediated axonal growth. J Neurosci. 2013;33:12728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lei H, Ma C, Liu Z, Gao S, Zhou L, Wang W, et al. USP47 is a new target in chronic myelogenous leukemia. Blood. 2015;126:1572.

    Article  Google Scholar 

  65. Li C, Wang Y, Gong Y, Zhang T, Huang J, Tan Z, et al. Finding an easy way to harmonize: A review of advances in clinical research and combination strategies of EZH2 inhibitors. Clin Epigenetics. 2021;13:62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gulati N, Béguelin W, Giulino-Roth L. Enhancer of zeste homolog 2 (EZH2) inhibitors. Leuk Lymphoma. 2018;59:1574–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tiffen JC, Gunatilake D, Gallagher SJ, Gowrishankar K, Heinemann A, Cullinane C, et al. Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes. Oncotarget. 2015;6:27023–36.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Wang Y-C, Wu Y-S, Hung C-Y, Wang S-A, Young M-J, Hsu T-I, et al. USP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and β-TrCP and promotes cancer malignancy. Nat Commun. 2018;9:3996.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Ovaa H, Kessler BM, Rolén U, Galardy PJ, Ploegh HL, Masucci MG. Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Proc Natl Acad Sci USA. 2004;101:2253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Nathanael Gray for his generous provision of reagents and technical support, and Lucia Cabal-Hierro at Dana-Farber Cancer Institute—Harvard Medical School for valuable guidance for the CRISPR-CAS9 KO assay. Our work was supported and founded by National Natural Science Foundation of China (Grant Nos. 82104198, 81903659, 32171479), Natural Science Foundation of Anhui Province (Grant No. 1908085MH259), Leukemia & Lymphoma Society’s New Idea Award, Claudia Adams Barr Award, MPN Research Foundation, Gabrielle’s Angel Foundation, NIH Foundation R01 (CA211681) and 5 P50 CA206963-02.

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  1. These authors contributed equally: Jing Yang, Ellen L. Weisberg, Shuang Qi.

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  1. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, PR China

    Jing Yang, Shuang Qi, Husheng Mei, Zuowei Wang, Mingqi Hou, Ziping Qi, Aoli Wang, Yunyun Jiang, Zongru Jiang, Tao Huang, Qingwang Liu, Wenchao Wang, Jing Liu & Qingsong Liu

  2. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, PR China

    Jing Yang, Shuang Qi, Ziping Qi, Aoli Wang, Yunyun Jiang, Zongru Jiang, Tao Huang, Qingwang Liu, Wenchao Wang, Jing Liu & Qingsong Liu

  3. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Jing Yang, Robert S. Magin, Laura Doherty & Sara J. Buhrlage

  4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Jing Yang, Robert S. Magin, Laura Doherty & Sara J. Buhrlage

  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Ellen L. Weisberg, Wei Ni, Chengcheng Meng, Shengzhe Zhang & James D. Griffin

  6. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Ellen L. Weisberg, Wei Ni, Chengcheng Meng, Shengzhe Zhang & James D. Griffin

  7. University of Science and Technology of China, Hefei, Anhui, 230036, PR China

    Husheng Mei, Zuowei Wang, Mingqi Hou & Qingsong Liu

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Contributions

JY, EW, and SQ conceptualized, designed, and performed the studies. JY, EW, and SQ carried out data analyses and wrote the papers. WN performed the KD assays and westerns in DLBCL. HM performed the cell viability assays and westerns. ZW helped with the generation of lentivirus particles and site mutagenesis assay. CM helped with cell culturing and western blotting. SZ assisted with shRNA KD/KO studies. MH helped with cell viability assays and westerns. ZQ and AW provided valuable scientific feedback and guidance. YJ synthesized compounds for animal studying. ZJ provided human PBMCs. TH provided human AML and DLBCL patient samples. QL measured the concentration of the compound in tissue. RM provided valuable scientific feedback. LD helped with qPCR assays. WW and JL provided valuable scientific feedback and guidance. SB, QL and JG conceptualized and designed the studies, carried out data analyses, and wrote the manuscript.

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Correspondence to Sara J. Buhrlage, Qingsong Liu or James D. Griffin.

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Yang, J., Weisberg, E.L., Qi, S. et al. Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2. Leukemia 36, 1048–1057 (2022). https://doi.org/10.1038/s41375-021-01494-w

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