Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition
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 h...
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| Veröffentlicht in: | Cancer discovery 2020-10, Vol.10 (10), p.1500-1513 |
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| creator | Cai, Sheng F Chu, S Haihua Goldberg, Aaron D Parvin, Salma Koche, Richard P Glass, Jacob L Stein, Eytan M Tallman, Martin S Sen, Filiz Famulare, Christopher A Cusan, Monica Huang, Chun-Hao Chen, Chun-Wei Zou, Lihua Cordner, Keith B DelGaudio, Nicole L Durani, Vidushi Kini, Mitali Rex, Madison Tian, Helen S Zuber, Johannes Baslan, Timour Lowe, Scott W Rienhoff, Jr, Hugh Y Letai, Anthony Levine, Ross L Armstrong, Scott A |
| description | 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
(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
progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1
leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for
in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant
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.
.
. |
| doi_str_mv | 10.1158/2159-8290.CD-19-1469 |
| format | Article |
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(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
progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1
leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for
in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant
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.
.
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(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
progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1
leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for
in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant
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.
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Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor
(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
progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1
leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for
in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant
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.
.
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| title | Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition |
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