Author:
Silvestri Giovannino,Trotta Rossana,Stramucci Lorenzo,Ellis Justin J.,Harb Jason G.,Neviani Paolo,Wang Shuzhen,Eisfeld Ann-Kathrin,Walker Christopher,Zhang Bin,Srutova Klara,Gambacorti-Passerini Carlo,Pineda Gabriel,Jamieson Catriona H. M.,Stagno Fabio,Vigneri Paolo,Nteliopoulos Georgios,May Philippa,Reid Alistair,Garzon Ramiro,Roy Denis C.,Moutuou Moutua-Mohamed,Guimond Martin,Hokland Peter,Deininger Michael,Fitzgerald Garrett,Harman Christopher,Dazzi Francesco,Milojkovic Dragana,Apperley Jane F.,Marcucci Guido,Qi Janfei,Machova-Polakova Katerina,Zou Ying,Fan Xiaoxuan,Baer Maria R.,Calabretta Bruno,Perrotti Danilo
Abstract
ABSTRACTDrug-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.
Publisher
Cold Spring Harbor Laboratory