Ezh2 Controls an Early Hematopoietic Program and Growth and Survival Signaling in Early T Cell Precursor Acute Lymphoblastic Leukemia. Cell Rep 2016 Mar 01;14(8):1953-65
Date
02/26/2016Pubmed ID
26904942Pubmed Central ID
PMC4790111DOI
10.1016/j.celrep.2016.01.064Scopus ID
2-s2.0-84959182180 (requires institutional sign-in at Scopus site) 52 CitationsAbstract
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.
Author List
Danis E, Yamauchi T, Echanique K, Zhang X, Haladyna JN, Riedel SS, Zhu N, Xie H, Orkin SH, Armstrong SA, Bernt KM, Neff TAuthor
Nan Zhu PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDisease Models, Animal
Enhancer of Zeste Homolog 2 Protein
Gene Expression Regulation, Leukemic
Genes, ras
Histones
Humans
Interleukin-6
Janus Kinase 1
Mice
Mice, Transgenic
Phosphorylation
Polycomb Repressive Complex 2
Precursor Cells, T-Lymphoid
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Receptors, Interleukin-6
STAT3 Transcription Factor
Signal Transduction
Transcription, Genetic
