title: GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia.
abstract: Initial pathway alternations required for pathogenesis of human acute myeloid leukemia (AML) are poorly understood. Here we reveal that removal of glycogen synthase kinase-3α (GSK-3α) and GSK-3β dependency leads to aggressive AML. Although GSK-3α deletion alone has no effect, GSK-3β deletion in hematopoietic stem cells (HSCs) resulted in a pre-neoplastic state consistent with human myelodysplastic syndromes (MDSs). Transcriptome and functional studies reveal that each GSK-3β and GSK-3α uniquely contributes to AML by affecting Wnt/Akt/mTOR signaling and metabolism, respectively. The molecular signature of HSCs deleted for GSK-3β provided a prognostic tool for disease progression and survival of MDS patients. Our study reveals that GSK-3α- and GSK-3β-regulated pathways can be responsible for stepwise transition to MDS and subsequent AML, thereby providing potential therapeutic targets of disease evolution.
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Borhane
authors.initials: B
authors.lastname: Guezguez
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Oncology, Juravinski Cancer Center, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Almakadi
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Yannick D
authors.initials: YD
authors.lastname: Benoit
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Shapovalova
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Susann
authors.initials: S
authors.lastname: Rahmig
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Aline
authors.initials: A
authors.lastname: Fiebig-Comyn
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Fanny L
authors.initials: FL
authors.lastname: Casado
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Borko
authors.initials: B
authors.lastname: Tanasijevic
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padua, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bresolin
authors.affiliation: Department of Pediatric Oncology and Hematology, University of Bologna, Bologna, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Masetti
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Doble
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; McMaster Stem Cell and Cancer Research Institute (SCC-RI), Michael G. DeGroote School of Medicine, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada. Electronic address: mbhatia@mcmaster.ca.
authors.forename: Mickie
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha