Researchers in ScienceTM discover how the loss of a microRNA can drive the transformation of leukemia stem cells—and find that restoring the microRNA miR-31-5p can eliminate these cells and suppress leukemia growth in mice.
Leukemia stem cells originate from hematopoietic stem cells , but our understanding of this transformation is limited. Here, Zhu and colleagues identified the microRNA miR-31-5p as a controller of the mode of energy metabolism in HSCs: Loss of miR-31-5p led to a transition away from glycolytic metabolism to oxidative phosphorylation, accumulation of the oncometabolite fumarate, and development of LSCs, whereas ectopic expression of miR-31-5p could eliminate LSCs.
Inhibition of miR-31-5p in HSPCs promotes the expression of its target gene, encoding FIH [factor inhibiting hypoxia-inducing factor 1α ], to suppress HIF-1α signaling. Increased FIH resulted in a switch from glycolysis to oxidative phosphorylation as the predominant mode of energy metabolism and increased the abundance of the oncometabolite fumarate. Increased fumarate promoted the conversion of HSPCs to LSCs and initiated myeloid leukemia-like disease in NOD-Prkdc/Bcgen mice.
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