Mitochondrial RNA degradation is increased in AML and controls differentiation, stem cell function and sensitivity to immune-mediated killing [RNA-seq]

Eukaryotic cells have two separate genomes that are replicated independently; nuclear DNA organized in chromosomes and circular DNA within mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA). As a by-product of the bi-directional transcription, dsRNA is also generated. By gene expression analysis and functional studies, we demonstrated that mtRNA transcription and degradation were increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discovered that the mitochondrial degradosome, SUV3 and PNPase, was upregulated in AML cells and stem cells and functionally important for the degradation of mtRNA and mitochondrial dsRNA in AML. Depleting SUV3 or PNPase impaired mtRNA degradation and promoted the accumulation of dsRNA. dsRNA that accumulated after depleting SUV3 or PNPase, stimulated IFN-I signaling that induced AML differentiation, decreased stem cell function and increased sensitivity of AML cells to immune-mediating killing. Thus, this work highlights new mitochondrial biology in AML and a novel mechanism by which the turnover of mtRNA regulates AML differentiation and stem cell function Overall design: Double-strand RNA (dsRNA) was extracted from AML cell line OCI AML-2 using immunoproecipation. Samples were extracted from 3 biological replicates after SUV3 knock-down and from 3 biological replicated after PNPT1 knock-down