3064 – ALKBH5 MODULATES HEMATOPOIETIC STEM AND PROGENITOR CELL ENERGY METABOLISM THROUGH M6A MODIFICATION-MEDIATED RNA STABILITY CONTROL

• Published in: Experimental hematology Vol. 124; p. S82
• Main Authors: Gao, Yimeng, Biancon, Giulia, Flavell, Richard, Gbyli, Rana, Halene, Stephanie, Kibbey, Richard, Li, Hua-Bing, Li, Yaping, Liu, Chengyang, Liu, Wei, Nelakanti, Raman, Patel, Amisha, Qi, Zhihong, Simon, Matthew, Slavoff, Sarah, Song, Yuanbin, Tebaldi, Toma, Vasic, Radovan, Xiao, Andrew, Zheng, Shu-Jian, Zimmer, Joshua
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 2023
• Subjects: Advanced Basic Science; Hematology, Oncology, and Palliative Medicine
• ISSN: 0301-472X
• DOI: 10.1016/j.exphem.2023.06.171

During hematopoietic differentiation from hematopoietic stem cells (HSCs) to mature blood cells, cells undergo a metabolic shift from glycolysis to mitochondrial respiration. The mechanisms by which hematopoietic cells adjust their energy metabolism are still under investigation. N6-mehyladenosine (m6A) mRNA modification has been reported to regulate numerous cellular processes. ALKBH5, the specific RNA m6A demethylase, becomes highly expressed in hematopoietic progenitors during hematopoietic development but the physiological role of ALKBH5 during hematopoiesis remains unknown. We generated Vav-iCre+; Alkbh5fl/fl (vcAlkbh5–/–) mice to delete of Alkbh5 in the hematopoietic system. vcAlkbh5–/– mice showed no hematopoietic defects at steady states. We applied TimeLapse-seq on lineage-depleted bone marrow cells of WT and vcAlkbh5–/– mice to determine whether loss of ALKBH5 perturbed mRNA stability. Ogdh mRNA was the most destabilized transcript resulting in significantly reduced OGDH protein levels. OGDH is the rate-limiting enzyme in the tricarboxylic acid (TCA) cycle. Inhibition of OGDH subsequently induces production of L-2-hydroxyglutarate (L-2-HG), whose metabolism is closely coupled to energy metabolism. We measured L- and D-2-HG in the plasma of WT and vcAlkbh5–/– mice, and confirmed that L-2-HG levels were significantly increased in the plasma of vcAlkbh5–/– mice. We next found that reduction of OGDH expression impaired energy metabolism via perturbation of the TCA cycle and oxidative phosphorylation (OXPHOS) in the mitochondria. In conclusion, our study demonstrates that ALKBH5 modulates energy metabolism by regulating mRNA stability of metabolic enzymes through its m6A demethylation activity during hematopoiesis. This finding links Alkbh5 expression kinetics to the metabolic shift from glycolysis to mitochondrial OXPHOS during hematopoietic development.