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The tumor suppressor gene PTEN encodes a lipid phosphatase that negatively regulates the PI3 Kinase (PI3K)-AKT signaling pathway and participates in fundamental cellular processes and tumorigenesis. The involvement of PTEN in regulating embryonic and neural stem cells as well as primordial germ cells has been studied recently. However, its role in regulation of hematopoietic stem cells (HSC) and the development of HSC-related hematological diseases remains elusive. Here we demonstrate that conditional disruption of the murine PTEN gene in HSC leads to a preferential expansion of PTEN null HSC and myeloid progenitor cells at the expense of B cell lineage. PTEN loss results in the development of a myeloproliferative disorder (MPD), which inevitably progresses from a chronic phase to a lethal leukemic blast crisis. Although treatment with rapamycin, a specific inhibitor for PI3K/AKT downstream effector mTOR, attenuates the expansion of PTEN-deficient lineage cells and delays leukemic progression, animals eventually relapse with leukemia/lymphoma following inhibitor withdrawal. In this two-phase MPD, leukemogenesis appears to require accumulation of additional molecular alteration(s), e.g. dysregulated Wnt/β-catenin signaling, in the PTEN null hematopoietic cells. Our study suggests a critical role for PTEN in the regulation of HSC function and provides molecular insights for the possible “second hit” in leukemogenesis.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]