Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions.

Autor:	Silvestri G; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland., Trotta R; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland., Stramucci L; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland., Ellis JJ; Department of Molecular Virology Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.; Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Harb JG; Department of Molecular Virology Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.; Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Neviani P; Department of Molecular Virology Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.; Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Wang S; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland., Eisfeld AK; Department of Molecular Virology Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.; Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Walker CJ; Department of Molecular Virology Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.; Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Zhang B; Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, California., Srutova K; Institute of Hematology and Blood Transfusion, University of Prague, Prague, Czech Republic., Gambacorti-Passerini C; Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy., Pineda G; Department of Health Sciences, School of Health and Human Services, National University, San Diego, California., Jamieson CHM; Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, California., Stagno F; Division of Hematology and Unit of Medical Oncology, A.O.U. 'Policlinico-Vittorio Emanuele', University of Catania, Catania, Italy., Vigneri P; Division of Hematology and Unit of Medical Oncology, A.O.U. 'Policlinico-Vittorio Emanuele', University of Catania, Catania, Italy., Nteliopoulos G; Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom., May PC; Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom., Reid AG; Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom., Garzon R; Department of Molecular Virology Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.; Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Roy DC; Department of Hematology and Cellular Therapy Laboratory, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec, Canada., Moutuou MM; Department of Hematology and Cellular Therapy Laboratory, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec, Canada., Guimond M; Department of Hematology and Cellular Therapy Laboratory, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec, Canada., Hokland P; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark., Deininger MW; Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Fitzgerald G; Center for Advanced Fetal Care University, University of Maryland School of Medicine, Baltimore, Maryland., Harman C; Center for Advanced Fetal Care University, University of Maryland School of Medicine, Baltimore, Maryland., Dazzi F; Division of Cancer Studies, Rayne Institute, King's College London, London, United Kingdom., Milojkovic D; Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom., Apperley JF; Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom., Marcucci G; Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, California., Qi J; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland., Polakova KM; Institute of Hematology and Blood Transfusion, University of Prague, Prague, Czech Republic., Zou Y; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland., Fan X; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland., Baer MR; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland., Calabretta B; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Perrotti D; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland. dperrotti@som.umaryland.edu.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.; Department of Haematology, Hammersmith Hospital, Imperial College London, London, United Kingdom.; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Blood cancer discovery [Blood Cancer Discov] 2020 Jul; Vol. 1 (1), pp. 48-67.
DOI:	10.1158/0008-5472.BCD-19-0039
Abstrakt:	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. Competing Interests: Disclosure of Potential Conflicts of Interest D. Perrotti has ownership interest in patents 8,633,161; 9,220,706 and 8,318,812. P. Neviani has ownership interest in patents 9,220,706; 8,633,161. C.J. Walker is a consultant at Karyopharm Therapeautics, Inc. F. Stagno has received speakers bureau honoraria from Novartis, Bristol-Myers Squibb, Pfizer, and Incyte. P. Vigneri reports receiving a commercial research grant from Novartis, has received speakers bureau honoraria from Incyte, is a consultant/advisory board member for Incyte. M.W. Deininger is a consultant/advisory board member at Blueprint, Fusion Pharma, Novartis, Sangamo, Takeda, Medscape, Incyte, Ascentage Pharma, Humana, TRM and reports receiving commercial research grants from Blueprint, Takeda, Novartis, Incyte, SPARC, Leukemia & Lymphoma Society, and Pfizer. D. Milojkovic has received speakers bureau honoraria from Novartis, Bristol-Myers Squibb, Incyte, and Pfizer. No potential conflicts of interest were disclosed by the other authors.
Databáze:	MEDLINE
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