miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response.
Blood
; 129(23): 3074-3086, 2017 06 08.
Article
in En
| MEDLINE
| ID: mdl-28432220
ABSTRACT
FLT3-ITD+ acute myeloid leukemia (AML) accounts for â¼25% 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interferons
/
MicroRNAs
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Fms-Like Tyrosine Kinase 3
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Myeloproliferative Disorders
Type of study:
Etiology_studies
Limits:
Animals
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Female
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Humans
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Male
Language:
En
Journal:
Blood
Year:
2017
Document type:
Article