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Title: Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling.

Authors: Varney, Melinda E; Niederkorn, Madeline; Konno, Hiroyasu; Matsumura, Takayuki; Gohda, Jin; Yoshida, Nobuaki; Akiyama, Taishin; Christie, Susanne; Fang, Jing; Miller, David; Jerez, Andres; Karsan, Aly; Maciejewski, Jaroslaw P; Meetei, Ruhikanta A; Inoue, Jun-ichiro; Starczynowski, Daniel T

Published In J Exp Med, (2015 Oct 19)

Abstract: TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) myelodysplastic syndrome (MDS). Deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cell (HSPC) proportions and altered myeloid differentiation. A subset of mice transplanted with Tifab knockout (KO) HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPCs are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic defect. Gene expression analysis of Tifab KO HSPCs identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. TIFAB forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPCs by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.

PubMed ID: 26458771 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis; Bone Marrow Transplantation; Cell Differentiation; Chromosomes, Human, Pair 5; Hematopoiesis*; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; MicroRNAs/physiology; NF-kappa B/antagonists & inhibitors; NF-kappa B/physiology; Proteins/genetics; Proteins/physiology*; Signal Transduction/physiology*; TNF Receptor-Associated Factor 6/physiology*; Toll-Like Receptors/physiology*

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