Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2010-01

AUTHORS

Daniel T Starczynowski, Florian Kuchenbauer, Bob Argiropoulos, Sandy Sung, Ryan Morin, Andrew Muranyi, Martin Hirst, Donna Hogge, Marco Marra, Richard A Wells, Rena Buckstein, Wan Lam, R Keith Humphries, Aly Karsan

ABSTRACT

5q- syndrome is a subtype of myelodysplastic syndrome characterized by severe anemia and variable neutropenia but normal or high platelet counts with dysplastic megakaryocytes. We examined expression of microRNAs (miRNAs) encoded on chromosome 5q as a possible cause of haploinsufficiency. We show that deletion of chromosome 5q correlates with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a, and we identify Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) and tumor necrosis factor receptor-associated factor-6 (TRAF6) as respective targets of these miRNAs. TIRAP is known to lie upstream of TRAF6 in innate immune signaling. Knockdown of miR-145 and miR-146a together or enforced expression of TRAF6 in mouse HSPCs resulted in thrombocytosis, mild neutropenia and megakaryocytic dysplasia. A subset of mice transplanted with TRAF6-expressing marrow progressed either to marrow failure or acute myeloid leukemia. Thus, inappropriate activation of innate immune signals in HSPCs phenocopies several clinical features of 5q- syndrome. More... »

PAGES

49-58

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nm.2054

DOI

http://dx.doi.org/10.1038/nm.2054

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1021915407

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19898489


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