Abstract 4775: PI3K-p110β is required for leukemic transformation and HSC depletion in the absence of Pten

Abstract

Abstract The tumor suppressor PTEN, which antagonizes PI3K signaling, plays critical roles in cell cycle, cell migration and stem cell self-renewal. PTEN is frequently mutated or inactivated in T-cell acute lymphoblastic leukemia (T-ALL) and acute myelogenous leukemia (AML). In mice, HSC-specific deletion of Pten leads to myeloproliferative phenotype, transplantable leukemia, and increased cycling of hematopoietic stem cells (HSCs), leading to their depletion. Rapamycin, an mTOR inhibitor, rescues this phenotype. Thus, it is likely that PI3K itself plays an important role in Pten-deficient HSCs and leukemic cells, but the specific contributions of the PI3K isoforms are poorly understood. We demonstrate that genetic ablation or pharmacological inhibition of PI3K-p110β prevents myeloid neoplasia and prolongs survival. Importantly, p110β ablation rescues HSCs in the bone marrow (BM), and reinstates long-term hematopoietic reconstitution. Moreover, Pten deficiency leads to aberrant expression of Cxcl12 in the BM and spleen, enabling the generation of an alternative splenic niche. Inactivation of p110β rescues retention of HSCs, and perturbs the splenic niche by interfering with the Cxcl12-CXCR4 axis. This suggests that selective inhibition of p110β offers an alternative therapeutic strategy in PTEN deficient leukemias while restoring untransformed HSCs to their proper niche. Citation Format: Haluk Yuzugullu, Lukas Baitsch, Allison Steiner, Linda K. Clayton, Kira Gritsman, Jean J. Zhao. PI3K-p110β is required for leukemic transformation and HSC depletion in the absence of Pten. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4775. doi:10.1158/1538-7445.AM2014-4775