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

TitleRegulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication
Authors
Issue Date27-May-2022
PublisherSpringer Nature [academic journals on nature.com]
Citation
Leukemia, 2022, v. 36, p. 1990-2001 How to Cite?
Abstract

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, KRASG12D, 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.


Persistent Identifierhttp://hdl.handle.net/10722/338944
ISSN
2023 Impact Factor: 12.8
2023 SCImago Journal Rankings: 3.662
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMan, CH-
dc.contributor.authorZeng, XY-
dc.contributor.authorLam, W-
dc.contributor.authorNg, TCC-
dc.contributor.authorKwok, TH-
dc.contributor.authorDang, KCC-
dc.contributor.authorLeung, TWY-
dc.contributor.authorNg, NKL-
dc.contributor.authorLam, SSY-
dc.contributor.authorCher, CY-
dc.contributor.authorLeung, AYH-
dc.date.accessioned2024-03-11T10:32:43Z-
dc.date.available2024-03-11T10:32:43Z-
dc.date.issued2022-05-27-
dc.identifier.citationLeukemia, 2022, v. 36, p. 1990-2001-
dc.identifier.issn0887-6924-
dc.identifier.urihttp://hdl.handle.net/10722/338944-
dc.description.abstract<p>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<sup>G12D</sup>, 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.</p>-
dc.languageeng-
dc.publisherSpringer Nature [academic journals on nature.com]-
dc.relation.ispartofLeukemia-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleRegulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication-
dc.typeArticle-
dc.identifier.doi10.1038/s41375-022-01606-0-
dc.identifier.scopuseid_2-s2.0-85130800255-
dc.identifier.volume36-
dc.identifier.spage1990-
dc.identifier.epage2001-
dc.identifier.eissn1476-5551-
dc.identifier.isiWOS:000805485900002-
dc.identifier.issnl0887-6924-

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