Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors

Therapeutic resistance of acute myeloid leukemia stem cells, enriched in the CD34(+)38(-)123(+) progenitor population, is supported by extrinsic factors such as the bone marrow niche. Here, we report that when adherent onto fibronectin or osteoblast components, CD34(+)38(-)123(+) progenitors survive through an integrin-dependent activation of glycogen synthase kinase 3 beta (GSK3 beta) by serine 9-dephosphorylation. Strikingly, GSK3 beta-mediated survival was restricted to leukemic progenitors from female patients. GSK3 beta inhibition restored sensitivity to etoposide, and impaired the clonogenic capacities of adherent leukemic progenitors from female patients. In leukemic progenitors from female but not male patients, the scaffolding protein RACK1, activated downstream of alpha 5 beta 1- integrin engagement, was specifically upregulated and controlled GSK3 beta activation through the phosphatase protein phosphatase 2A (PP2A). In a mirrored manner, survival of adherent progenitors (CD34(+)38(-)) from male but not female healthy donors was partially dependent on this pathway. We conclude that the GSK3 beta-dependent survival pathway might be sex-specific in normal immature population and flip-flopped upon leukemogenesis. Taken together, our results strengthen GSK3 beta as a promising target for leukemic stem cell therapy and reveal gender differences as a new parameter in anti-leukemia therapy. Oncogene (2012) 31, 694-705; doi:10.1038/onc.2011.258; published online 4 July 2011