SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.

Document Type

Article

Publication Date

3-2024

Identifier

DOI: 10.1038/s41556-024-01349-3

Abstract

Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT-β-catenin pathway. The increase in PFKP elevates energy metabolic activities and, as a consequence, enhances the sensitivity of LSCs to chemotherapeutic agents. Moreover, the upregulation of PFKP promotes MYC degradation and, consequently, reduces the immune evasion abilities of LSCs. Overall, our study demonstrates that targeting SHP-1 disrupts the metabolic balance in LSCs, thereby increasing their vulnerability to chemotherapy and immunosurveillance. This approach offers a promising strategy to overcome LSC resistance in acute myeloid leukaemia.

Journal Title

Nature cell biology

Volume

26

Issue

3

First Page

464

Last Page

477

MeSH Keywords

Humans; Metabolic Reprogramming; Monitoring, Immunologic; Leukemia, Myeloid, Acute; Stem Cells; Neoplastic Stem Cells

Keywords

Metabolic Reprogramming; Immunologic Monitoring; Acute Myeloid Leukemia; Stem Cells; Neoplastic Stem Cells

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