Synapse - Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition

Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition Journal Article

Authors:	Cai, S. F.; Chu, S. H.; Goldberg, A. D.; Parvin, S.; Koche, R. P.; Glass, J. L.; Stein, E. M.; Tallman, M. S.; Sen, F.; Famulare, C. A.; Cusan, M.; Huang, C. H.; Chen, C. W.; Zou, L.; Cordner, K. B.; DelGaudio, N. L.; Durani, V.; Kini, M.; Rex, M.; Tian, H. S.; Zuber, J.; Baslan, T.; Lowe, S. W.; Rienhoff, H. Y. Jr; Letai, A.; Levine, R. L.; Armstrong, S. A.
Article Title:	Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition
Abstract:	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.
Keywords:	genes; differentiation; expression; stem-cells; activation; acute myeloid-leukemia; progenitor; mitochondrial; evi1; venetoclax
Journal Title:	Cancer Discovery
Volume:	10
Issue:	10
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2020-10-01
Start Page:	1500
End Page:	1513
Language:	English
ACCESSION:	WOS:000576792800025
DOI:	10.1158/2159-8290.Cd-19-1469
PROVIDER:	wos
PMCID:	PMC7584353
PUBMED:	32606137
Notes:	Article -- Source: Wos