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Learn MoreInterstitial deletion of a single copy of chromosome 5q is the most frequent cytogenetic alteration in Myelodysplastic Syndromes (MDS), which results in reduced dosage of numerous genes. Furthermore, the extent of the 5q deletion determines disease severity, suggesting cooperation between deleted genes in the proximal and distal regions of del(5q). Although the contribution of individual genes to the pathogenesis of del(5q) MDS has been investigated, less is known about the epistatic interactions and/or cooperation between neighboring deleted genes. Deletion of TRAF-interacting protein with forkhead-associated domain B (TIFAB) and miR-146a, two haploinsufficient genes in del(5q) MDS, has been previously reported to activate the Toll-like receptor (TLR) signaling cascade in hematopoietic stem/progenitor cells (HSPC) by increasing TRAF6 protein stability and mRNA translation, respectively. To investigate the epistasis of TIFAB and miR-146a, we generated a mouse model in which Tifab and miR-146a were simultaneously deleted (Tifab-/-;miR-146a-/-, dKO). Herein, we report that combined hematopoietic-specific deletion of Tifab and miR-146a results in more rapid and severe cytopenia, and progression to a fatal bone marrow (BM) failure-like disease as compared to Tifab- or miR-146adeficiency alone. HSPC from Tifab-/-, miR-146a-/-, and dKO mice exhibit enrichment of gene 69 regulatory networks associated with innate immune signaling. Moreover, a subset of the differentially expressed genes is controlled synergistically following deletion of Tifab and miR-146a. Notably, nearly half of these defined synergy response genes identified in the mouse models were aberrantly expressed in del(5q) MDS HSPC when TIFAB (5q31) and miR-146a (5q33.3) were both deleted. Thus, synergistic control of gene expression following deletion of epistatic haploinsufficient genes in del(5q) MDS may be an underlying mechanism of the diseased state. SOURCE: Daniel Starczynowski (daniel.starczynowski@cchmc.org) - Starczynowski CCHMC
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