Self-renewal is the central property of stem cells but remains inadequately defined. Separately, the Pten/Akt and Wnt/β-catenin signaling pathways have been implicated in regulating hematopoietic stem cells (HSCs) and in leukemia development. Using an HSC-specific conditional mutant model, we studied the effects of Pten deletion combined with constitutively active β-catenin. HSC-specific deletion of Pten leads to a relatively moderate HSC expansion in spleen with increased myeloid differentiation. In contrast, HSC-specific activation of β-catenin results in functional failure by differentiation blockage. However, unlike single mutants, double mutant mice exhibit a novel phenotype including dramatic expansion in HSCs without extensive differentiation both in vitro and in vivo. Furthermore, β-catenin deficiency prevents the relatively moderate expansion of HSCs in Pten mutants. Our data reveal that these two pathways interact to coordinately drive HSC proliferation while inhibiting both differentiation and apoptosis. Together, the Pten/Akt and Wnt/β-catenin pathways cooperate to drive self-renewal, with uncontrolled self-renewal leading to leukemia development.

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