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Regulation and Function of TIFAB in Myelodysplastic Syndrome

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Final rept. 1 Jun 2011-30 May 2014

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Myelodysplastic syndromes MDS are clonal bone marrow failure BMF disorders defined by blood cytopenias due to ineffective hematopoiesis, genomic instability, and a predisposition to acute myeloid leukemia AML. The most commonly recurring genomic alteration in MDS is deletion of chromosome 5q del5q. MDS patients with an isolated del5q presenting with anemia, neutropenia, and elevated platelets associated with dysplastic megakaryocytes are considered to have 5q- syndrome. The majority of MDS patients with del5q do not exhibit these particular symptoms and, instead, are referred to as del5q MDS . We have recently identified miR- 146a, which target the TRAF6 arm of the innate immune pathway, a gene within the deleted region in del5q MDS. We posit that multiple genes on chr 5q coordinate TRAF6 activation in del5q MDS. A search of annotated genes within or near the CDRs revealed a known inhibitor of TRAF6, TIFAB, on band q31.1. We hypothesize that deletion of TIFAB promotes activation of the TRAF6 complex in human CD34 cells resulting in hematopoietic defects resembling MDS with del5q. The overall objectives of this proposal are to 1 determine whether loss of TIFAB in human CD34 cells contributes to MDS in mice 2 to investigate whether deletions of TIFAB activate TRAF6 in MDS and 3 to determine the consequences of TIFAB deletion on signal transduction in human CD34 cells, and whether these could explain features of MDS. In preliminary data from the first 2 year of the proposal, we have evidence that TIFAB is a regulator of human hematopoietic cells. Our key observations show that knockdown of TIFAB in human CD34 hematopoietic stemprogenitor cells results in increased survival and proliferation, TIFAB inhibits TRAF6 protein expression and activation, resulting in lower NF-B activation, and TIFAB expression impacts leukemic cell survival, growth and progenitor function.

Subject Categories:

  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research

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