The 14q32.31 DLK1-DIO3 MIR300 tumor suppressor promotes 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-imprinted MIR300 is 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. MIR300 anti-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 limits MIR300 functions to cytostasis by regulating unbound-MIR300 levels. Halting MIR300 homeostasis restores NK cell activity and suppresses leukemic but not normal hematopoiesis by eradicating nearly all LSCs. Thus, MIR300 tumor suppressor activity is essential and therapeutically important for LSC-driven leukemias.