ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control
Yimeng Gao, Joshua T. Zimmer, Radovan Vasic, Chengyang Liu, Rana Gbyli, Shu-Jian Zheng, Amisha Patel, Wei Liu, Zhihong Qi, Yaping Li, Raman Nelakanti, Yuanbin Song, Giulia Biancon, Andrew Xiao, Sarah A. Slavoff, Richard G. Kibbey, Richard A. Flavell, Matthew D. Simon, Toma Tebaldi, Huabing Li, Stephanie Halene
Abstract
N 6 -methyladenosine (m 6 A) 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 m 6 A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m 6 A-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 m 6 A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.