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.
Myelodysplastic syndromes (MDS) are a collection of diseases wherein the bone marrow produces too few blood cells. Most of these patients have a deletion of chromosome 5q. We have identified a gene, TIFAB, on chromosome 5q, that when deleted, may play a role in the abnormal production of blood cells. This grant is designed to understand the function of TIFAB and to determine its role in causing MDS using mouse models.
|GaÃ±Ã¡n-GÃ³mez, I; Wei, Y; Starczynowski, D T et al. (2015) Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia 29:1458-69|
|Adams, Allie K; Bolanos, Lyndsey C; Dexheimer, Phillip J et al. (2015) IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival. Oncotarget 6:43395-407|
|Rhyasen, G W; Starczynowski, D T (2015) IRAK signalling in cancer. Br J Cancer 112:232-7|
|Varney, Melinda E; Niederkorn, Madeline; Konno, Hiroyasu et al. (2015) Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med 212:1967-85|
|Varney, Melinda E; Melgar, Katelyn; Niederkorn, Madeline et al. (2015) Deconstructing innate immune signaling in myelodysplastic syndromes. Exp Hematol 43:587-98|
|Rhyasen, G W; Wunderlich, M; Tohyama, K et al. (2014) An MDS xenograft model utilizing a patient-derived cell line. Leukemia 28:1142-5|
|Starczynowski, Daniel T (2014) Errant innate immune signaling in del(5q) MDS. Blood 124:669-71|
|Beverly, Levil J; Starczynowski, Daniel T (2014) IRAK1: oncotarget in MDS and AML. Oncotarget 5:1699-700|
|Fang, Jing; Barker, Brenden; Bolanos, Lyndsey et al. (2014) Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-ÎºB gene network. Cell Rep 8:1328-38|
|Zhao, Jimmy L; Starczynowski, Daniel T (2014) Role of microRNA-146a in normal and malignant hematopoietic stem cell function. Front Genet 5:219|
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