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miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response.

  • Author(s): Wallace, Jared A
  • Kagele, Dominique A
  • Eiring, Anna M
  • Kim, Carissa N
  • Hu, Ruozhen
  • Runtsch, Marah C
  • Alexander, Margaret
  • Huffaker, Thomas B
  • Lee, Soh-Hyun
  • Patel, Ami B
  • Mosbruger, Timothy L
  • Voth, Warren P
  • Rao, Dinesh S
  • Miles, Rodney R
  • Round, June L
  • Deininger, Michael W
  • O'Connell, Ryan M
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465836/
No data is associated with this publication.
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.

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