Loss of Tifab, a del(5q) MDS Gene, Alters Hematopoiesis Through Derepression of Toll-like receptor-TRAF6 Signaling

J Exp Med. 2015 Oct 19;212(11):1967-85. doi: 10.1084/jem.20141898. Epub 2015 Oct 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Bone Marrow Transplantation
  • Cell Differentiation
  • Chromosomes, Human, Pair 5
  • Hematopoiesis*
  • Humans
  • 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*

Substances

  • MicroRNAs
  • Mirn146 microRNA, mouse
  • NF-kappa B
  • Proteins
  • TIFAB protein, mouse
  • TNF Receptor-Associated Factor 6
  • Tifab protein, human
  • Toll-Like Receptors