Regulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication.

Autor: Man CH; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China. csman729@hku.hk., Zeng X; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Lam W; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Ng TCC; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Kwok TH; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Dang KCC; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Leung TWY; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Ng NKL; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Lam SSY; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Cher CY; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China., Leung AYH; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China. ayhleung@hku.hk.; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China. ayhleung@hku.hk.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2022 Aug; Vol. 36 (8), pp. 1990-2001. Date of Electronic Publication: 2022 May 27.
DOI: 10.1038/s41375-022-01606-0
Abstrakt: Gain-of-function kinase mutations are common in AML and usually portend an inferior prognosis. We reported a novel mechanism whereby kinase mutants induced intracellular alkalization characteristic in oncogenesis. Thirteen kinases were found to activate sodium/hydrogen exchanger (NHE1) in normal hematopoietic progenitors, of which FLT3-ITD, KRAS G12D , and BTK phosphorylated NHE1 maintained alkaline intracellular pH (pHi) and supported survival of AML cells. Primary AML samples with kinase mutations also showed increased NHE1 phosphorylation and evidence of NHE1 addiction. Amiloride enhanced anti-leukemic effects and intracellular distribution of kinase inhibitors and chemotherapy. Co-inhibition of NHE1 and kinase synergistically acidified pHi in leukemia and inhibited its growth in vivo. Plasma from patients taking amiloride for diuresis reduced pHi of leukemia and enhanced cytotoxic effects of kinase inhibitors and chemotherapy in vitro. NHE1-mediated intracellular alkalization played a key pathogenetic role in transmitting the proliferative signal from mutated-kinase and could be exploited for therapeutic intervention in AML.
(© 2022. The Author(s).)
Databáze: MEDLINE
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