Leukemia cell of origin influences apoptotic priming and sensitivity to lsd1 inhibition

Sheng F. Cai, S. Haihua Chu, Aaron D. Goldberg, Salma Parvin, Richard P. Koche, Jacob L. Glass, Eytan M. Stein, Martin S. Tallman, Filiz Sen, Christopher A. Famulare, Monica Cusan, Chun Hao Huang, Chun Wei Chen, Lihua Zou, Keith B. Cordner, Nicole L. Delgaudio, Vidushi Durani, Mitali Kini, Madison Rex, Helen S. TianJohannes Zuber, Timour Baslan, Scott W. Lowe, Hugh Y. Rienhoff, Anthony Letai, Ross L. Levine*, Scott A. Armstrong

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1500-1513
Number of pages14
JournalCancer discovery
Issue number10
StatePublished - 2020

ASJC Scopus subject areas

  • Oncology


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