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

Autor:	Danis E; Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA., Yamauchi T; Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA., Echanique K; Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA., Zhang X; Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA., Haladyna JN; Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA., Riedel SS; Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA., Zhu N; Stem Cell Biology and Hematopoiesis Program, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA., Xie H; Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA., Orkin SH; Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA., Armstrong SA; Cancer Biology and Genetics Program, Departments of Medicine and Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Bernt KM; Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO 80045, USA. Electronic address: kathrin.bernt@ucdenver.edu., Neff T; Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO 80045, USA. Electronic address: tobias.neff@ucdenver.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2016 Mar 01; Vol. 14 (8), pp. 1953-65. Date of Electronic Publication: 2016 Feb 18.
DOI:	10.1016/j.celrep.2016.01.064
Abstrakt:	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. (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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