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dc.contributor.advisorRoss Levine
dc.contributor.authorCai, Sheng F
dc.contributor.authorChu, S Haihua
dc.contributor.authorGoldberg, Aaron D
dc.contributor.authorParvin, Salma
dc.contributor.authorKoche, Richard P
dc.contributor.authorGlass, Jacob L
dc.contributor.authorStein, Eytan M
dc.contributor.authorTallman, Martin S
dc.contributor.authorSen, Filiz
dc.contributor.authorFamulare, Christopher A
dc.contributor.authorCusan, Monica
dc.contributor.authorHuang, Chun-Hao
dc.contributor.authorChen, Chun-Wei
dc.contributor.authorZou, Lihua
dc.contributor.authorCordner, Keith B
dc.contributor.authorDelGaudio, Nicole L
dc.contributor.authorDurani, Vidushi
dc.contributor.authorKini, Mitali
dc.contributor.authorRex, Madison
dc.contributor.authorTian, Helen S
dc.contributor.authorZuber, Johannes
dc.contributor.authorBaslan, Timour
dc.contributor.authorLowe, Scott W
dc.contributor.authorRienhoff, Hugh Y
dc.contributor.authorLetai, Anthony
dc.contributor.authorLevine, Ross L
dc.contributor.authorArmstrong, Scott A
dc.date.accessioned2022-10-28T19:20:41Z
dc.date.available2022-10-28T19:20:41Z
dc.date.issued2020-06-30
dc.identifier.citationCai SF, Chu SH, Goldberg AD, Parvin S, Koche RP, Glass JL, Stein EM, Tallman MS, Sen F, Famulare CA, Cusan M, Huang CH, Chen CW, Zou L, Cordner KB, DelGaudio NL, Durani V, Kini M, Rex M, Tian HS, Zuber J, Baslan T, Lowe SW, Rienhoff HY Jr, Letai A, Levine RL, Armstrong SA. Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition. Cancer Discov. 2020 Oct;10(10):1500-1513. doi: 10.1158/2159-8290.CD-19-1469. Epub 2020 Jun 30. PMID: 32606137; PMCID: PMC7584353.en_US
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.CD-19-1469en_US
dc.identifier.pmid32606137
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51228
dc.descriptionHelen Tian participated in this study as a medical student in the Senior Scholars research program at UMass Chan Medical School.en_US
dc.description.abstractThe 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 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 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.en_US
dc.language.isoenen_US
dc.relation.ispartofCancer Discoveryen_US
dc.relation.urlhttps://doi.org/10.1158/2159-8290.cd-19-1469en_US
dc.rights©2020 American Association for Cancer Research.en_US
dc.titleLeukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibitionen_US
dc.typeJournal Articleen_US
dc.source.journaltitleCancer discovery
dc.source.volume10
dc.source.issue10
dc.source.beginpage1500
dc.source.endpage1513
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.identifier.journalCancer discovery
dc.contributor.departmentT.H. Chan School of Medicineen_US
dc.contributor.studentChun-Wei Chen
dc.description.thesisprogramNeuroscience


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