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

Key Points

• miR-155 promotes myeloproliferation in the bone marrow, spleen, and blood of mice carrying the FLT3-ITD mutation.

• miR-155 suppresses the IFN response in FLT3-ITD ⁺ mouse hematopoietic stem and progenitor cells, as well as FLT3-ITD ⁺ human AML cells.

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.