miR-126 governs human leukemia stem cell quiescence and therapeutic resistance

In acute myeloid leukemia (AML), leukemia stem cells (LSC) play a central role in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. Whereas epigenetic regulation balances normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic modifiers are now considered fundamental to leukemia initiation and progression. Alterations in miRNA function represent a non-canonical epigenetic mechanism influencing malignant hematopoiesis, however the function of miRNA in LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly predictive of patient survival. Gain of function genetic analysis demonstrated that miR-126 restrained cell cycle progression, prevented LSC differentiation, and increased LSC self-renewal. miR-126 promoted chemo-resistance, preserving LSC quiescence in part through suppression of the G0 to G1 gatekeeper, CDK3. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC. 74 primary patient normal karyotype AML samples were analyzed for miRNA expression.