Ezh2 Controls an Early Hematopoietic Program and Growth and Survival Signaling in Early T Cell Precursor Acute Lymphoblastic Leukemia

Cell Rep. 2016 Mar 1;14(8):1953-65. doi: 10.1016/j.celrep.2016.01.064. Epub 2016 Feb 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Enhancer of Zeste Homolog 2 Protein / deficiency
  • Enhancer of Zeste Homolog 2 Protein / genetics*
  • Gene Expression Regulation, Leukemic*
  • Genes, ras*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / metabolism
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Polycomb Repressive Complex 2 / deficiency
  • Polycomb Repressive Complex 2 / genetics*
  • Polycomb Repressive Complex 2 / metabolism
  • Precursor Cells, T-Lymphoid / metabolism
  • Precursor Cells, T-Lymphoid / pathology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription, Genetic

Substances

  • Eed protein, mouse
  • Histones
  • Interleukin-6
  • Receptors, Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Suz12 protein, mouse
  • interleukin-6, mouse
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Polycomb Repressive Complex 2
  • Jak1 protein, mouse
  • Janus Kinase 1