@article{072cb97dc8a84a4399e76069c8e108c0,
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 sensi-tivity, but the mechanisms governing cell-of-origin–driven differences in therapeu-tic 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 activ-ity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional out-put, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic lo stresses. p53 loss of function in Evi1 progenitor-derived leukemias induces resistance to LSD1 inhibi-tion, 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 hi drug resistance in chemoresistant EVI1 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.",
author = "Cai, {Sheng F.} and Chu, {S. Haihua} and Goldberg, {Aaron D.} and Salma Parvin and Koche, {Richard P.} and Glass, {Jacob L.} and Stein, {Eytan M.} and Tallman, {Martin S.} and Filiz Sen and Famulare, {Christopher A.} and Monica Cusan and Huang, {Chun Hao} and Chen, {Chun Wei} and Lihua Zou and Cordner, {Keith B.} and Delgaudio, {Nicole L.} and Vidushi Durani and Mitali Kini and Madison Rex and Tian, {Helen S.} and Johannes Zuber and Timour Baslan and Lowe, {Scott W.} and Rienhoff, {Hugh Y.} and Anthony Letai and Levine, {Ross L.} and Armstrong, {Scott A.}",
note = "Funding Information: We thank members of the Levine, Armstrong, and Lowe laboratories for discussions. We thank Yanming Zhang for assistance with cytogenetic analysis of AML patient samples. S.F. Cai was supported by a Scholar Award from the American Society of Hematology, a Momentum Fellowship Award from The Mark Foundation for Cancer Research, a Young Investigator Award from The Truth 365 and the Rally Foundation for Childhood Cancer Research, a Young Investigator Award from the Conquer Cancer Foundation, a Career Development Program Fellow Award (545317) from the Leukemia & Lymphoma Society, and a Memorial Sloan Kettering Cancer Center Clinical Scholars Biomedical Research Fellowship. R.L. Levine was supported by NCI grants P01 CA108671 and R35197594 as well as a Leukemia & Lymphoma Society Specialized Center of Research grant. S.A. Armstrong was supported by grants from the NIH, NCI grants PO1 CA66996 and R01 CA140575, and Gabrielle{\textquoteright}s Angel Research Foundation. Studies supported by Memorial Sloan Kettering core facilities were supported, in part, by Memorial Sloan Kettering Cancer Center Support Grant/Core Grant P30 CA008748. Funding Information: S.F. Cai reports grants from American Society of Hematology, The Mark Foundation for Cancer Research, The Truth 365/Rally Foundation for Childhood Cancer Research, Conquer Cancer Foundation, and Leukemia & Lymphoma Society, and other support from Imago Biosciences (consultancy) during the conduct of the study, and personal fees and non-financial support from DAVA Oncology outside the submitted work. A.D. Goldberg reports grants, personal fees, and non-financial support from AbbVie and Daiichi Sankyo (outside the submitted work), grants and personal fees from Aptose, personal fees from Celgene, Genentech, and Dava Oncology (outside the submitted), work grants and non-financial support from ADC Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
doi = "10.1158/2159-8290.CD-19-1469",
language = "English (US)",
volume = "10",
pages = "1500--1513",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "10",
}
