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

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  • 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.


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

publication date

  • January 2016