Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that MIR300 has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. MIR300 is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates MIR300 in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating TUG1 long noncoding RNA that uncouples and limits MIR300 function to cytostasis. Genetic and pharmacologic MIR300 modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis in vitro and in patient-derived xenografts; hence, the importance of MIR300 and PP2A activity for CML development and therapy.

Center for Advanced Fetal Care University University of Maryland School of Medicine Baltimore Maryland

Department of Biochemistry and Molecular Biology University of Maryland School of Medicine Baltimore Maryland

Department of Haematology Hammersmith Hospital Imperial College London London United Kingdom

Department of Health Sciences School of Health and Human Services National University San Diego California

Department of Hematology Aarhus University Hospital Aarhus Denmark

Department of Hematology and Cellular Therapy Laboratory Hôpital Maisonneuve Rosemont University of Montreal Montreal Quebec Canada

Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus Ohio

Department of Medicine and Moores Cancer Center University of California San Diego La Jolla California

Department of Medicine University of Maryland School of Medicine Baltimore Maryland

Department of Microbiology and Immunology University of Maryland School of Medicine Baltimore Maryland

Department of Molecular Virology Immunology and Medical Genetics The Ohio State University Comprehensive Cancer Center Columbus Ohio

Division of Cancer Studies Rayne Institute King's College London London United Kingdom

Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute University of Utah Salt Lake City Utah

Division of Hematology and Unit of Medical Oncology A O U Policlinico Vittorio Emanuele University of Catania Catania Italy

Division of Hematopoietic Stem Cell and Leukemia Research City of Hope National Medical Center Duarte California

Hematology and Clinical Research Unit San Gerardo Hospital Monza Italy

Institute of Hematology and Blood Transfusion University of Prague Prague Czech Republic

Marlene and Stewart Greenebaum Comprehensive Cancer Center University of Maryland School of Medicine Baltimore Maryland

Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia Pennsylvania

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Blood Cancer Discov. 2020 Jun 22;1(1):13-15. doi: 10.1158/2643-3249.BCD-20-0034. PubMed

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