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Proton shifting induces cell growth and is exploited in leukemia by epigenetic enforcement of H+/lactate-cotransporter expression

ABSTRACT: Ion balance is critical for membrane polarity, signaling and bioenergesis in cells. Here, we report that proton distribution resets metabolism and alters growth in hematopoietic cells. Multiple oncogenic mutations in acute myeloid leukemia utilize proton partitioning to enhance growth by epigenetically upregulating H+/lactate-co-transporter, MCT4, shuttling protons extracellularly to increase intracellular pH. Secondarily, activity of metabolic enzymes (hexokinase, pyruvate kinase and glucose-6-phosphate dehydrogenase) is increased, raising carbon flux through glycolysis and pentose phosphate pathway necessary for proliferation. MCT4-overexpression in normal hematopoietic stem and progenitor cells increases growth without malignant transformation. Yet, inhibiting MCT4 in AML decreases pHi and carbon flux that improves animal survival and, unexpectedly, elimination of leukemic initiating cells in vivo. AML with increased MCT4 expression have activating histone mark, H3K27ac, in MCT4 promoter where MLL-AF9 and BRD4 directly bind. These data demonstrate the sequential alteration of metabolism through epigenetic activation of proton regulator and point to cytoplasmic alkalization as a growth promoting strategy exploited by malignant cells. Inhibiting this process may diminish the competitive advantage of leukemia and potentially improve AML treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE124696 | GEO | 2020/12/31

REPOSITORIES: GEO

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Proton shifting induces cell growth and is exploited in leukemia by epigenetic enforcement of H+/lactate-cotransporter expression

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