TY - JOUR T1 - The 14q32.31 <em>DLK1-DIO3 MIR300 tumor suppressor</em> promotes leukemogenesis by inducing cancer stem cell quiescence and inhibiting NK cell anti-cancer immunity JF - bioRxiv DO - 10.1101/680108 SP - 680108 AU - Giovannino Silvestri AU - Rossana Trotta AU - Lorenzo Stramucci AU - Justin J. Ellis AU - Jason G. Harb AU - Paolo Neviani AU - Shuzhen Wang AU - Ann-Kathrin Eisfeld AU - Christopher Walker AU - Bin Zhang AU - Klara Srutova AU - Carlo Gambacorti-Passerini AU - Gabriel Pineda AU - Catriona H. M. Jamieson AU - Fabio Stagno AU - Paolo Vigneri AU - Georgios Nteliopoulos AU - Philippa May AU - Alistair Reid AU - Ramiro Garzon AU - Denis C. Roy AU - Moutua-Mohamed Moutuou AU - Martin Guimond AU - Peter Hokland AU - Michael Deininger AU - Garrett Fitzgerald AU - Christopher Harman AU - Francesco Dazzi AU - Dragana Milojkovic AU - Jane F. Apperley AU - Guido Marcucci AU - Janfei Qi AU - Katerina Machova-Polakova AU - Ying Zou AU - Xiaoxuan Fan AU - Maria R. Baer AU - Bruno Calabretta AU - Danilo Perrotti Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/06/23/680108.abstract N2 - 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. ER -