3050 – DELETION OF PHOSPHOINOSITIDE 3-KINASE DYSREGULATES AUTOPHAGY IN HEMATOPOIETIC STEM CELLS AND PROMOTES MYELOID DYSPLASIA

Adult hematopoietic stem cells (HSCs) maintain blood system through a delicate equilibrium between self-renewal and differentiation. Most hematopoietic growth factors and cytokines signal through the phosphoinositide 3-kinase (PI3K) pathway via three Class IA catalytic PI3K isoforms (P110α, β, and δ). However, it is not known if PI3K is required for HSC differentiation or self-renewal. We found that individual PI3K isoforms are dispensable in HSCs. To determine the redundant roles of PI3K isoforms in HSCs, we generated a triple knockout (TKO) mouse model with conditional deletion of P110α and P110β in hematopoietic cells, and germline deletion of P110δ. TKO mice develop transplantable pancytopenia, and TKO bone marrow cells have defective long-term multilineage repopulation. Surprisingly, we observed a significant expansion of donor TKO HSCs in transplant recipients. TKO bone marrow cells have decreased myeloid differentiation capacity and extended serial re-plating activity. Additionally, TKO bone marrow cells have dysplastic features similar to those seen in myelodysplastic syndrome (MDS) with multiple chromosomal abnormalities. For the maintenance of self-renewal of HSCs autophagy was shown to be essential. However, in TKO HSCs upon serum starvation autophagy is defective. Surprisingly, we found that in TKO cKit+ cells MTOR signaling is hyperactivated. Given that MTOR is a negative regulator of autophagy, this is consistent with the decrease in autophagy in TKO HSCs. The MTOR inhibitor rapamycin can induce autophagy in TKO HSCs, which rescues the self-renewal and differentiation defects caused by PI3K deletion. Our results uncover important roles of PI3K in regulating autophagy induction in HSCs to maintain the balance between self-renewal and differentiation. This work has potential implications for the treatment of MDS by regulating autophagy induction.