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PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway

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机构： [']Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA [2]Department of Biological Chemistry and Molecular Pharmacology, Harvard MedicalSchool, Boston, MA, USA [3]Hongqiao International Institute of Medicine， Shanghai Tongren Hospital, KeyLaboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education,Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine,Shanghai, China [4]Department of Epidemiology, Harvard T.H.Chan School of Public Health, Boston,MA, USA [5]Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA [6]Department of Pathology and Medicine, University of California, San Diego, La Jolla,CA, USA [7]Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [8]Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA [9]Broad Institute of Harvard and MIT, Cambridge, MA, USA [10]Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA

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Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem/progenitor cells. AML prognosis remains poor, due to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The PI3K/AKT pathway is often dysregulated in AML. We found while that PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes NRF2 nuclear accumulation, which induces 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.Copyright © 2024 American Society of Hematology.

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出版当年[2023]版：

大类 | 1 区

医学

小类 | 1 区血液学

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区血液学

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出版当年[2022]版：

Q1 HEMATOLOGY

最新[2023]版：

Q1 HEMATOLOGY

影响因子： 21.1 最新[2023版] 19.2 最新五年平均 20.3 出版当年[2022版] 19.6 出版当年五年平均 25.669 出版前一年[2021版] 21.1 出版后一年[2023版]

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第一作者机构： [2]Department of Biological Chemistry and Molecular Pharmacology, Harvard MedicalSchool, Boston, MA, USA

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通讯机构： [2]Department of Biological Chemistry and Molecular Pharmacology, Harvard MedicalSchool, Boston, MA, USA [9]Broad Institute of Harvard and MIT, Cambridge, MA, USA [10]Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA [*1]450 Brookline Avenue, Boston, MA 02215, USA

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