The 14q32.31DLK1-DIO3 MIR300 tumor suppressorpromotes leukemogenesis by inducing cancer stem cell quiescence and inhibiting NK cell anti-cancer immunity

Drug-resistance of tumor-initiating cells, impaired NK cell immune-response, PP2A loss-of-function and aberrant miRNA expression are cancer features resulting from microenvironmental- and tumor-specific signals. Here we report that genomic-imprintedMIR300is a cell context-independent dual function tumor suppressor which is upregulated in quiescent leukemic stem (LSC) and NK cells by microenvironmental signals to induce quiescence and impair immune-response, respectively, but inhibited in CML and AML proliferating blasts to prevent PP2A-induced apoptosis.MIR300anti-proliferative and PP2A-activating functions are differentially activated through dose-dependent CCND2/CDK6 and SET inhibition, respectively. LSCs escape PP2A-mediated apoptosis through TUG1 lncRNA that uncouples and limitsMIR300functions to cytostasis by regulating unbound-MIR300levels. HaltingMIR300homeostasis restores NK cell activity and suppresses leukemic but not normal hematopoiesis by eradicating nearly all LSCs. Thus,MIR300tumor suppressor activity is essential and therapeutically important for LSC-driven leukemias.