Identification and characterization of genes in del(5q) myelodysplastic syndrome

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DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are clonal marrow failure disorders defined by blood cytopenias due to ineffective hematopoiesis, genomic instability, and predisposition to leukemia. The most recurring genomic alteration in MDS is deletion of chromosome 5q (del(5q)). Two common deleted regions (CDRs) have been mapped on chr 5q (bands q31.1 and q33.1); however, the genes within the CDRs that contribute to dysplastic myeloid cells or to a survival advantage for hematopoietic stem/progenitor cells (HSPC) have not been identified. We recently identified miR-146a, which is near the distal CDR, to be significantly reduced in del(5q) MDS patients. Loss of miR-146a or overexpression of its target, TRAF6, in HSPC results in an MDS-like disease in mice. A search of annotated genes within or near the CDRs revealed another known inhibitor of TRAF6, TRAF-interacting protein with forkhead-associated domain B (TIFAB), on 5q31.1 (within the proximal CDR). TIFAB binds and inhibits TIFA, a protein essential for TRAF6 activation. We hypothesize that TIFAB deletion results in HSPC defects contributing to del(5q) MDS by promoting hyperactivation of TRAF6, and propose that simultaneous loss of TIFAB and miR-146a synergistically activate TRAF6 in HSPC to induce a more accurate disease. Preliminary data show that RNAi-mediated knockdown or genetic deletion of TIFAB results in MDS-like defects in mice. The objectives of this proposal are (1) to investigate the loss of TIFAB on HSPC function and the contribution to MDS; (2) to determine the consequences of TIFAB deletion on TRAF6 activation, and whether these could explain features of MDS; and (3) to investigate whether deletions of TIFAB and miR-146a cooperate to initiate MDS via TRAF6 activation. Given that the molecular basis of MDS is poorly defined, we hope that characterization of TIFAB will facilitate understanding the molecular defects and the design of novel therapeutics in MDS.