PI3K γ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway

Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem or progenitor cells. AML prognosis remains poor owing to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often dysregulated in AML. We found that although PI3K gamma is highly enriched in LSCs and critical for self -renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3K gamma- AKT signaling promotes nuclear factor erythroid 2 -related factor 2 (NRF2) nuclear accumulation, which induces 6-phosphogluconate dehydrogenase (PGD) and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3K gamma impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our fi ndings reveal a key role for PI3K gamma in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3K gamma pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.