Journal ArticleDOI
Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype
Daniel T. Starczynowski,Florian Kuchenbauer,Bob Argiropoulos,Sandy Sung,Ryan D. Morin,Andrew L Muranyi,Martin Hirst,Donna E. Hogge,Marco A. Marra,Richard A. Wells,Rena Buckstein,Wan L. Lam,R. Keith Humphries,Aly Karsan +13 more
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TLDR
Deletes chromosome 5q and identifies Toll–interleukin-1 receptor domain–containing adaptor protein (TIRAP) and tumor necrosis factor receptor–associated factor-6 (TRAF6) as respective targets of these miRNAs.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.read more
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Journal ArticleDOI
Mouse models of myelodysplastic syndromes.
TL;DR: Several MDS mouse models are described and advances made are discussed in the understanding of the different disease mechanisms within the malignant clone and the marrow microenvironment, and progress in xenotransplantation models of MDS is described.
Journal ArticleDOI
Myelodysplastic syndrome hematopoietic stem cell.
TL;DR: The prevailing model suggests that genetic and/or epigenetic alterations that occur in H SCs or HSC niche compromise HSC function, resulting in MDS; therefore, MDS HSCs are likely the ideal targets for MDS treatment.
Journal ArticleDOI
Hsp90 Inhibition Reduces TLR5 Surface Expression and NF-κB Activation in Human Myeloid Leukemia THP-1 Cells
TL;DR: The results suggest that Hsp90 inhibitors suppress TLR5 surface expression and activation of NF-κB in THP-1 cells in response toTLR5 ligand, and these inhibitory effects may be associated with the possible mechanisms by which Hsp 90 inhibitors suppress myeloid leukemia.
Journal ArticleDOI
microRNA regulation in megakaryocytopoiesis
TL;DR: This review summarizes the miRNAs which have changed expression during megakaryocytopoiesis, and their positive and negative functions on megakARYocytic differentiation.
Journal ArticleDOI
The role of haploinsufficiency of RPS14 and p53 activation in the molecular pathogenesis of the 5q- syndrome.
TL;DR: A mouse model of the human 5q- syndrome generated by large-scale deletion of the Cd74-Nid67 interval (containing RPS14) further supports a critical role for R PS14 haploinsufficiency and emerging data suggests that the p53 activation observed in the mouse model may also apply to the human5q- Syndrome.
References
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TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
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TL;DR: A role is proposed for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor- associated factor 6 protein levels.
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TAK1 is a ubiquitin-dependent kinase of MKK and IKK
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MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells
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