GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia

Borhane Guezguez; Mohammed Almakadi; Yannick D Benoit; Zoya Shapovalova; Susann Rahmig; Aline Fiebig-Comyn; Fanny L Casado; Borko Tanasijevic; Silvia Bresolin; Riccardo Masetti; Bradley W Doble; Mickie Bhatia

doi:10.1016/j.ccell.2015.11.012

GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia

Cancer Cell. 2016 Jan 11;29(1):61-74. doi: 10.1016/j.ccell.2015.11.012.

Affiliations

¹ McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Hamilton, ON L8N 3Z5, Canada.
² 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.
³ Department of Women's and Children's Health, University of Padova, Padua, Italy.
⁴ Department of Pediatric Oncology and Hematology, University of Bologna, Bologna, Italy.
⁵ 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.
⁶ 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.

PMID: 26766591
DOI: 10.1016/j.ccell.2015.11.012

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Glycogen Synthase Kinase 3 / deficiency
Glycogen Synthase Kinase 3 / metabolism*
Glycogen Synthase Kinase 3 beta
Hematopoietic Stem Cells / enzymology*
Humans
Leukemia, Myeloid, Acute / enzymology*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / therapy
Mice, Transgenic
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction / physiology

Substances

GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Proto-Oncogene Proteins c-akt
Glycogen Synthase Kinase 3
glycogen synthase kinase 3 alpha

Grants and funding

Canadian Institutes of Health Research/Canada