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

Autor:	Cai SF; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.; Leukemia Service, Department of Medicine, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Chu SH; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Goldberg AD; Leukemia Service, Department of Medicine, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Parvin S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Koche RP; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York., Glass JL; Leukemia Service, Department of Medicine, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Stein EM; Leukemia Service, Department of Medicine, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Tallman MS; Leukemia Service, Department of Medicine, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Sen F; Hematopathology Diagnostic Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Famulare CA; Leukemia Service, Department of Medicine, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Cusan M; University Hospital, Ludwig Maximilian University Munich, Munich, Germany., Huang CH; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York., Chen CW; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California., Zou L; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York., Cordner KB; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., DelGaudio NL; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Durani V; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Kini M; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Rex M; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Tian HS; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Zuber J; Research Institute of Molecular Pathology (IMP), Vienna, Austria., Baslan T; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York., Lowe SW; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.; Howard Hughes Medical Institute, New York, New York., Rienhoff HY Jr; Imago Biosciences, Inc., San Francisco, California., Letai A; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Levine RL; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. scott_armstrong@dfci.harvard.edu leviner@mskcc.org.; Leukemia Service, Department of Medicine, and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Armstrong SA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. scott_armstrong@dfci.harvard.edu leviner@mskcc.org.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2020 Oct; Vol. 10 (10), pp. 1500-1513. Date of Electronic Publication: 2020 Jun 30.
DOI:	10.1158/2159-8290.CD-19-1469
Abstrakt:	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. See related commentary by Gu et al., p. 1445 . This article is highlighted in the In This Issue feature, p. 1426 . (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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