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Publication

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.

Cell reports | 2023

N6-methyladenosine (m6A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m6A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.

Pubmed ID: 37742191 RIS Download

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Associated grants

Agency: Howard Hughes Medical Institute, United States
Agency: NIDDK NIH HHS, United States
Id: R01 DK102792
Agency: NIH HHS, United States
Id: S10 OD026996
Agency: NCI NIH HHS, United States
Id: R01 CA266604
Agency: NIDDK NIH HHS, United States
Id: U54 DK106857
Agency: NIDDK NIH HHS, United States
Id: R01 DK124788
Agency: NIDDK NIH HHS, United States
Id: P30 DK045735
Agency: NCI NIH HHS, United States
Id: R01 CA253981
Agency: NIGMS NIH HHS, United States
Id: R01 GM137117
Agency: NCI NIH HHS, United States
Id: P30 CA016359

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