PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.
Blood
; 143(19): 1965-1979, 2024 May 09.
Article
in En
| MEDLINE
| ID: mdl-38271660
ABSTRACT
ABSTRACT 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 PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-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 PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pentose Phosphate Pathway
/
Neoplastic Stem Cells
/
Leukemia, Myeloid, Acute
/
Class Ib Phosphatidylinositol 3-Kinase
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Blood
Year:
2024
Document type:
Article
Affiliation country: