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DNA damage-induced HSPC failure depends on ROS accumulation downstream of IFN-1 signaling and Bid mobilization

ABSTRACT: Targeted mouse mutants with inactivated Mixed-Lineage-Leukemia-5 (Mll5, MGI:1924825) alleles exhibit numerical, cell cycle and functional abnormalities in their hematopoietic stem and progenitor cell (HSPC) compartments, including hyper-proliferation of otherwise quiescent hematopoietic stem cells, lack of long-term reconstitution potential and profound radiation sensitivity. Most of the HSPC defects are secondary to increased levels of DNA damage and intracellular accumulation of reactive oxygen species (ROS). To obtain first insights into underlying molecular mechanisms, we performed Affymetrix gene chip analysis using total RNA isolated from FACS-sorted Lin-Sca1+Kit+ (LSK) cells of Mll5+/+ and Mll5-/- mice, both with and without prior long-term treatment with the ROS quencher N-Acetyl-L-Cysteine (NAC). As key finding, microarray data revealed elevated hybridization signals for several transcripts of known or putative IFN-1 target genes in LSK cells from Mll5-/- mice irrespective of NAC-treatment. In fact, comprehensive gene set enrichment analysis identified a number of gene sets closely associated with interferon responses that were significantly affected in Mll5-/- LSK cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE85076 | GEO | 2016/08/02

SECONDARY ACCESSION(S): PRJNA336057

REPOSITORIES: GEO

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Project description:TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) Myelodysplastic syndrome (MDS). Hematopoietic-specific deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cells (HSPC) proportions, altered myeloid differentiation, and progressive cytopenia. A subset of mice transplanted with Tifab knockout (KO) hematopoietic cells develop a bone marrow failure (BMF)-like disease with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPC are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic HSPC defect. Gene expression analysis of Tifab KO HSPC identified dysregulation of immune-related signatures, and hypersensitivity to Toll-like receptor 4 (TLR4) stimulation. TIFAB also 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 in HSPC, 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 in vivo. Re-expression of TIFAB in human del(5q) leukemic cells results in attenuated TLR4 signaling and reduced cell viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPC by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML. We performed an expression analysis on sorted lineage-Sca1+cKit+ (LSK) isolated from bone marrow (BM) of 3 month old mice transplanted with Tifab+/+ (WT) or Tifab-/- (KO) BM cells (n = 3 mice/group). We selected this time point to capture the gene expression profile of Tifab-/- LSK after engraftment but prior to overt hematopoietic failure. Total RNA was extracted, purified, reverse transcribed, labeled, and hybridized onto the GeneChip MoGene 2.0 ST Array (Affymetrix). Comparison comprises mRNA expression profile of Tifab+/+ LSK vs. Tifab-/- LSK.

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DNA damage-induced HSPC failure depends on ROS accumulation downstream of IFN-1 signaling and Bid mobilization

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