[PDF][PDF] Ezh2 controls an early hematopoietic program and growth and survival signaling in early T cell precursor acute lymphoblastic leukemia

E Danis, T Yamauchi, K Echanique, X Zhang… - Cell reports, 2016 - cell.com
E Danis, T Yamauchi, K Echanique, X Zhang, JN Haladyna, SS Riedel, N Zhu, H Xie
Cell reports, 2016cell.com
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 Ezh2 in a murine model of NRASQ61K-driven leukemia that recapitulates
phenotypic and transcriptional features of ETP-ALL. Homozygous inactivation of Ezh2 …
Summary
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 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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