Ezh2 Controls an Early Hematopoietic Program and Growth and Survival Signaling in Early T Cell Precursor Acute Lymphoblastic Leukemia
2016
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 Polycomb repressive complex 2 components are frequent in human ETP-ALL, but their functional role is largely undefined. We have studied the involvement of
Ezh2in a murine model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL. Homozygous inactivation of
Ezh2cooperated with oncogenic NRASQ61K to accelerate leukemia onset. Inactivation of
Ezh2accentuated expression of genes highly expressed in human ETP-ALL and in normal murine early thymic progenitors. Moreover, we found that
Ezh2contributes to the silencing of stem-cell- and early-progenitor-cell-associated genes. Loss of
Ezh2also resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. Our data mechanistically link
Ezh2inactivation to stem-cell-associated transcriptional programs and increased growth/survival signaling, features that convey an adverse prognosis in patients.
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