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 MENS HOODIES 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 Beach towels 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.