miR-126 Governs Human Leukemia Stem Cell Quiescence and Therapeutic Resistance [miRNA]

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 mechanisms balance normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic regulators are 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 human LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly prognostic for patient survival. Gain- and loss-of-function analyses demonstrated that miR-126 restrained cell cycle progression, prevented differentiation, and increased self-renewal of human LSC. By targeting the G0 to G1 gatekeeper CDK3, miR-126 preserved LSC quiescence and promoted chemotherapy resistance. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC. Peripheral blood from 24 AML patients and 3 human lin-CB pools were thawed, stained for CD34/CD38 cell surface markers and sorted into 4 populations. A total of 13 AML patient samples were functionally validated for leukemia-initiating capacity by xenotransplanation into immunodeficient mice. Global miRNA profiling was performed on all sorted AML samples and 3 lin-CB samples. An LSC miRNA signature was derived by infomatically testing engrafting fractions against non-engrafting fractions.