Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition

被引：31

作者：

Cai, Sheng F. ^{[1
,2
,3
]}

Chu, S. Haihua ^{[4
,5
]}

Goldberg, Aaron D. ^{[2
,3
]}

Parvin, Salma ^{[6
]}

Koche, Richard P. ^{[7
]}

Glass, Jacob L. ^{[2
,3
]}

Stein, Eytan M. ^{[2
,3
]}

Tallman, Martin S. ^{[2
,3
]}

Sen, Filiz ^{[8
]}

Famulare, Christopher A. ^{[2
,3
]}

Cusan, Monica ^{[9
]}

Huang, Chun-Hao ^{[10
]}

Chen, Chun-Wei ^{[11
]}

Zou, Lihua ^{[7
,15
]}

Cordner, Keith B. ^{[1
]}

DelGaudio, Nicole L. ^{[1
]}

Durani, Vidushi ^{[1
]}

Kini, Mitali ^{[1
]}

Rex, Madison ^{[1
]}

Tian, Helen S. ^{[1
]}

Zuber, Johannes ^{[12
]}

Baslan, Timour ^{[10
]}

Lowe, Scott W. ^{[10
,13
]}

Rienhoff, Hugh Y., Jr. ^{[14
]}

Letai, Anthony ^{[6
]}

Levine, Ross L. ^{[1
,2
,3
]}

Armstrong, Scott A. ^{[4
,5
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, 1275 York Ave, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Ctr Hematol Malignancies, 1275 York Ave, New York, NY 10021 USA

[4] Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[5] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[6] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[7] Mem Sloan Kettering Canc Ctr, Ctr Epigenet Res, 1275 York Ave, New York, NY 10021 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Pathol, Hematopathol Diagnost Serv, 1275 York Ave, New York, NY 10021 USA

[9] Ludwig Maximilian Univ Munich, Univ Hosp, Munich, Germany

[10] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA

[11] City Hope Natl Med Ctr, Dept Syst Biol, Beckman Res Inst, Duarte, CA USA

[12] Res Inst Mol Pathol IMP, Vienna, Austria

[13] Howard Hughes Med Inst, New York, NY USA

[14] Imago Biosci Inc, San Francisco, CA USA

[15] Northwestern Univ, Dept Biochem & Mol Genet, Feinberg Sch Med, Chicago, IL 60611 USA

来源：

CANCER DISCOVERY | 2020年 / 10卷 / 10期

关键词：

ACUTE MYELOID-LEUKEMIA; STEM-CELLS; EXPRESSION; DIFFERENTIATION; EVI1; PROGENITOR; GENES; MITOCHONDRIAL; VENETOCLAX; ACTIVATION;

D O I：

10.1158/2159-8290.CD-19-1469

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor MECOM (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for EVI1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic stresses. p53 loss of function in Evi1(lo) progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1(hi) leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1(hi) acute myeloid leukemia. SIGNIFICANCE: We demonstrate that the cell of origin of leukemia initiation influences p53 activity and dictates therapeutic sensitivity to pharmacologic LSD1 inhibitors via the transcription factor EVI1. We show that drug resistance could be overcome in HSC-derived leukemias by combining LSD1 inhibition with venetoclax.

引用

页码：1500 / 1513

页数：14

共 47 条

[1] p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2 [J].

Aliouat-Denis, CM ;

Dendouga, N ;

Van den Wyngaert, I ;

Goehlmann, H ;

Steller, U ;

van de Weyer, I ;

Van Slycken, N ;

Andries, L ;

Kass, S ;

Luyten, W ;

Janicot, M ;

Vialard, JE .

MOLECULAR CANCER RESEARCH, 2005, 3 (11) :627-634

[2] The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia [J].

Baker, Adele ;

Gregory, Gareth P. ;

Verbrugge, Inge ;

Kats, Lev ;

Hilton, Joshua J. ;

Vidacs, Eva ;

Lee, Erwin M. ;

Lock, Richard B. ;

Zuber, Johannes ;

Shortt, Jake ;

Johnstone, Ricky W. .

CANCER RESEARCH, 2016, 76 (05) :1158-1169

[3] Optimizing sparse sequencing of single cells for highly multiplex copy number profiling [J].

Baslan, Timour ;

Kendall, Jude ;

Ward, Brian ;

Cox, Hilary ;

Leotta, Anthony ;

Rodgers, Linda ;

Riggs, Michael ;

D'Italia, Sean ;

Sun, Guoli ;

Yong, Mao ;

Miskimen, Kristy ;

Gilmore, Hannah ;

Saborowski, Michael ;

Dimitrova, Nevenka ;

Krasnitz, Alexander ;

Harris, Lyndsay ;

Wigler, Michael ;

Hicks, James .

GENOME RESEARCH, 2015, 25 (05) :714-724

[4] MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L [J].

Bernt, Kathrin M. ;

Zhu, Nan ;

Sinha, Amit U. ;

Vempati, Sridhar ;

Faber, Joerg ;

Krivtsov, Andrei V. ;

Feng, Zhaohui ;

Punt, Natalie ;

Daigle, Amanda ;

Bullinger, Lars ;

Pollock, Roy M. ;

Richon, Victoria M. ;

Kung, Andrew L. ;

Armstrong, Scott A. .

CANCER CELL, 2011, 20 (01) :66-78

[5] Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia [J].

Bhola, Patrick D. ;

Mar, Brenton G. ;

Lindsley, R. Coleman ;

Ryan, Jeremy A. ;

Hogdal, Leah J. ;

Thanh Trang Vo ;

DeAngelo, Daniel J. ;

Galinsky, Ilene ;

Ebert, Benjamin L. ;

Letai, Anthony .

JOURNAL OF CLINICAL INVESTIGATION, 2016, 126 (10) :3827-3836

[6] EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs [J].

Bindels, Eric M. J. ;

Havermans, Marije ;

Lugthart, Sanne ;

Erpelinck, Claudia ;

Wocjtowicz, Elizabeth ;

Krivtsov, Andrei V. ;

Rombouts, Elwin ;

Armstrong, Scott A. ;

Taskesen, Erdogan ;

Haanstra, Jurgen R. ;

Beverloo, H. Berna ;

Doehner, Hartmut ;

Hudson, Wendy A. ;

Kersey, John H. ;

Delwel, Ruud ;

Kumar, Ashish R. .

BLOOD, 2012, 119 (24) :5838-5849

[7] Chromatin Signatures in Multipotent Human Hematopoietic Stem Cells Indicate the Fate of Bivalent Genes during Differentiation [J].

Cui, Kairong ;

Zang, Chongzhi ;

Roh, Tae-Young ;

Schones, Dustin E. ;

Childs, Richard W. ;

Peng, Weiqun ;

Zhao, Keji .

CELL STEM CELL, 2009, 4 (01) :80-93

[8] LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1-and C/EBPα-dependent enhancers in AML [J].

Cusan, Monica ;

Cai, Sheng F. ;

Mohammad, Helai P. ;

Krivtsov, Andrei ;

Chramiec, Alan ;

Loizou, Evangelia ;

Witkin, Matthew D. ;

Smitheman, Kimberly N. ;

Tenen, Daniel G. ;

Ye, Min ;

Will, Britta ;

Steidl, Ulrich ;

Kruger, Ryan G. ;

Levine, Ross L. ;

Rienhoff, Hugh Y., Jr. ;

Koche, Richard P. ;

Armstrong, Scott A. .

BLOOD, 2018, 131 (15) :1730-1742

[9] BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents [J].

Deng, Jing ;

Carlson, Nicole ;

Takeyama, Kunihiko ;

Dal Cin, Paola ;

Shipp, Margaret ;

Letai, Anthony .

CANCER CELL, 2007, 12 (02) :171-185

[10] Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia [J].

DiNardo, Courtney D. ;

Pratz, Keith ;

Pullarkat, Vinod ;

Jonas, Brian A. ;

Arellano, Martha ;

Becker, Pamela S. ;

Frankfurt, Olga ;

Konopleva, Marina ;

Wei, Andrew H. ;

Kantarjian, Hagop M. ;

Xu, Tu ;

Hong, Wan-Jen ;

Chyla, Brenda ;

Potluri, Jalaja ;

Pollyea, Daniel A. ;

Letai, Anthony .

BLOOD, 2019, 133 (01) :7-17

← 1 2 3 4 5 →