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PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cell through regulation of the pentose phosphate pathway

ABSTRACT: Leukemia stem cells (LSCs) are responsible for the initiation, progression, and recurrence of leukemia. Targeting LSCs is thought as an effective way to cure leukemia, for which it is pivotal to identify novel therapeutic targets. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is frequently activated in acute myeloid leukemia (AML) and strongly contributes to survival and proliferation of leukemia cells. Herein, we revealed that the p110γ isoform of PI3K was highly expressed in both mouse and human LSCs. Leukemogenesis was drastically delayed upon Pik3cg deletion during serial transplantations in murine acute myeloid leukemia models. Knockout of Pik3cg resulted in a remarkably impaired self-renewal, enhanced differentiation, and 32-fold reduced number of mouse acute myeloid LSCs. Interestingly, Pik3cg deficiency did not alter the functions of mouse hematopoietic stem cells. Mechanistically, PIK3CG/AKT/NRF2/PGD signaling axis controlled the pentose phosphate pathway to regulate redox metabolism and support nucleotide synthesis to maintain LSC fates. PIK3CG knockdown also led to a significant extended survival of recipients transplanted with human AML cells. Pharmaceutical inhibition of PIK3CG could efficiently restrain the progression of AML. PIK3CG may serve as a potential therapeutic target for the elimination of LSCs without influencing normal hematopoiesis.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE224607 | GEO | 2024/02/02

REPOSITORIES: GEO

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