RT Journal Article
SR Electronic
T1 Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition
JF Cancer Discovery
JO Cancer Discov
FD American Association for Cancer Research
SP 1500
OP 1513
DO 10.1158/2159-8290.CD-19-1469
VO 10
IS 10
A1 Cai, Sheng F.
A1 Chu, S. Haihua
A1 Goldberg, Aaron D.
A1 Parvin, Salma
A1 Koche, Richard P.
A1 Glass, Jacob L.
A1 Stein, Eytan M.
A1 Tallman, Martin S.
A1 Sen, Filiz
A1 Famulare, Christopher A.
A1 Cusan, Monica
A1 Huang, Chun-Hao
A1 Chen, Chun-Wei
A1 Zou, Lihua
A1 Cordner, Keith B.
A1 DelGaudio, Nicole L.
A1 Durani, Vidushi
A1 Kini, Mitali
A1 Rex, Madison
A1 Tian, Helen S.
A1 Zuber, Johannes
A1 Baslan, Timour
A1 Lowe, Scott W.
A1 Rienhoff, Hugh Y.
A1 Letai, Anthony
A1 Levine, Ross L.
A1 Armstrong, Scott A.
YR 2020
UL http://cancerdiscovery.aacrjournals.org/content/10/10/1500.abstract
AB 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 Evi1lo progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1hi 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 EVI1hi 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