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
RNA-binding proteins mind the GAPs.
TL;DR: Increased expression of the ubiquitin ligase TRAF6 in hematopoietic stem cells promotes activity of the GTP-binding protein Cdc42, which leads to an inability to properly process pre-mRNA encoding CDC42-inhibitory GTPase-activating proteins.
Role of Genetic Haploinsufficiency in the Biology and Targeted Therapy of Del(5q) Myelodysplastic Syndrome
TL;DR: The studies presented in this thesis focused on the identification of genes that play a central role in the pathogenesis of myelodysplastic syndromes with a deletion of the short arm of chromosome 5, the del(5q) MDS to gain a better understanding of how gene haploinsufficiency in (del)5q MDS leads to a clonal advantage, ineffective hematopoiesis and how haplo insufficiency can be targeted.
Journal ArticleDOI
Acute myeloid leukemia with isolated del(5q) is associated with IDH1/IDH2 mutations and better prognosis when compared to acute myeloid leukemia with complex karyotype including del(5q).
TL;DR: Clinopathologic characterization including mutation analysis was performed on acute myeloid leukemia with isolated del(5q) and it appeared to show some distinct clinicopathologic and genomic features as compared to cases of acuteMyeloidukemia with complex karyotype including del( 5q).
Journal ArticleDOI
Case records of the Massachusetts General Hospital. Case 27-2010. A 73-year-old woman with chronic anemia.
TL;DR: A 73-year-old woman was seen in the cancer center at this hospital for management of a myelodysplastic syndrome with isolated del(5q); she required red-cell transfusions every 2 months to maintain a hematocrit of 30.
Book ChapterDOI
Comparative Genomic Hybridization and Array Based CGH in Cancer
TL;DR: This chapter describes the development and current knowledge on aCGH technology and its role in cancer research and clinical diagnostics.
References
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TAK1 is a ubiquitin-dependent kinase of MKK and IKK
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