title: Ezh2 Controls an Early Hematopoietic Program and Growth and Survival Signaling in Early T Cell Precursor Acute Lymphoblastic Leukemia.
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.
authors.affiliation: Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Etienne
authors.initials: E
authors.lastname: Danis
authors.affiliation: Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Echanique
authors.affiliation: Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Haladyna
authors.affiliation: Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Simone S
authors.initials: SS
authors.lastname: Riedel
authors.affiliation: Stem Cell Biology and Hematopoiesis Program, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xie
authors.affiliation: Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Cancer Biology and Genetics Program, Departments of Medicine and Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: 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.
authors.forename: Kathrin M
authors.initials: KM
authors.lastname: Bernt
authors.affiliation: 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.
authors.forename: Tobias
authors.initials: T
authors.lastname: Neff
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000172:deficiency / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D011905:Genes, ras; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D054504:Precursor Cells, T-Lymphoid / Q000378:metabolism / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C107275:Eed protein, mouse; D006657:Histones; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494163:Suz12 protein, mouse; C577686:interleukin-6, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1