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Wallace, JA; Kagele, DA; Eiring, AM; Kim, CN; Hu, R; Runtsch, MC; Alexander, M; Huffaker, TB; Lee, SH; Patel, AB; Mosbruger, TL; Voth, WP; Rao, DS; Miles, RR; Round, JL; Deininger, MW; O'Connell, RM.
miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response.
Blood. 2017; 129(23): 3074-3086. Doi: 10.1182/blood-2016-09-740209 [OPEN ACCESS]
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Co-authors Med Uni Graz: Runtsch Marah
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Abstract:: FLT3-ITD⁺ acute myeloid leukemia (AML) accounts for ∼25% of all AML cases and is a subtype that carries a poor prognosis. microRNA-155 (miR-155) is specifically overexpressed in FLT3-ITD⁺ AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the growth of FLT3-ITD⁺ AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we used a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood. Mechanistically, miR-155 increases proliferation of the hematopoietic stem and progenitor cell compartments by reducing the growth-inhibitory effects of the interferon (IFN) response, and this involves targeting of Cebpb. Consistent with our observations in mice, primary FLT3-ITD⁺ AML clinical samples have significantly higher miR-155 levels and a lower IFN response compared with FLT3-WT AML samples. Further, inhibition of miR-155 in FLT3-ITD⁺ AML cell lines using CRISPR/Cas9, or primary FLT3-ITD⁺ AML samples using locked nucleic acid antisense inhibitors, results in an elevated IFN response and reduces colony formation. Altogether, our data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo and that this involves a multitarget mechanism that includes repression of IFN signaling.
Find related publications in this database (using NLM MeSH Indexing): Animals - administration & dosage; CRISPR-Cas Systems - administration & dosage; Cell Line, Tumor - administration & dosage; Disease Models, Animal - administration & dosage; Female - administration & dosage; Humans - administration & dosage; Interferons - biosynthesis; Leukemia, Myeloid, Acute - etiology, genetics, immunology; Male - administration & dosage; Mice - administration & dosage; Mice, Inbred C57BL - administration & dosage; Mice, Knockout - administration & dosage; Mice, Mutant Strains - administration & dosage; MicroRNAs - antagonists & inhibitors, genetics; Mutation - administration & dosage; Myeloid Progenitor Cells - immunology, pathology; Myelopoiesis - genetics; Myeloproliferative Disorders - etiology, genetics, immunology; Tumor Stem Cell Assay - administration & dosage; fms-Like Tyrosine Kinase 3 - genetics