Journal
CELL REPORTS
Volume 14, Issue 8, Pages 1953-1965Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.01.064
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Funding
- National Cancer Institute (NCI) [K08CA154777]
- University of Colorado Denver, Section for Pediatric Hematology/Oncology
- Cancer League Colorado
- Sidney Kimmel Foundation for Cancer Research
- National Heart, Lung, and Blood Institute [K08HL102264]
- NCI (Shared Resource of the University of Colorado Cancer Center) [P30CA046934]
- Children's Hospital Colorado Research Institute
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Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive subtype of ALL distinguished by stem-cell-associated and myeloid transcriptional programs. Inactivating alterations of Poly-comb repressive complex 2 components are frequent in human ETP-ALL, but their functional role is largely undefined. We have studied the involvement of Ezh2 in a murine model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL. Homozygous inactivation of Ezh2 cooperated with oncogenic NRASQ61K to accelerate leukemia onset. Inactivation of Ezh2 accentuated expression of genes highly expressed in human ETP-ALL and in normal murine early thymic progenitors. Moreover, we found that Ezh2 contributes to the silencing of stem-cell-and early-progenitor-cell-associated genes. Loss of Ezh2 also resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. Our data mechanistically link Ezh2 inactivation to stem-cell-associated transcriptional programs and increased growth/survival signaling, features that convey an adverse prognosis in patients.
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