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

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): 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
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.

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Teaser

Guezguez et al. show that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling by Gsk3b allelic deletion results in an MDS state that, when combined with Gsk3a deletion, leads to AML. A molecular signature derived from Gsk3b-null cells has prognostic potential for MDS patients.


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