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

摘要

Initial pathway alternations required for pathogenesis of human acute myeloid leukemia (AML) are poorly understood. Here we reveal that removal of glycogen synthase kinase-3 alpha (GSK-3 alpha) and GSK-3 beta dependency leads to aggressive AML. Although GSK-3 alpha deletion alone has no effect, GSK-3 beta 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-3 beta and GSK-3 alpha uniquely contributes to AML by affecting Wnt/Akt/mTOR signaling and metabolism, respectively. The molecular signature of HSCs deleted for GSK-3 beta provided a prognostic tool for disease progression and survival of MDS patients. Our study reveals that GSK-3 alpha- and GSK-3 beta-regulated pathways can be responsible for stepwise transition to MDS and subsequent AML, thereby providing potential therapeutic targets of disease evolution.