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Nfix is a novel regulator of murine hematopoietic stem and progenitor cell survival

ABSTRACT: Hematopoietic stem cells are both necessary and sufficient to sustain the complete blood system of vertebrates. Here we show that Nfix, a member of the nuclear factor I (Nfi) family of transcription factors, is highly expressed by hematopoietic stem and progenitor cells (HSPC) of murine adult bone marrow. Although shRNA mediated knockdown of Nfix expression in Lineage-Sca-1+c-Kit+ HSPC had no effect on in vitro cell growth or viability, Nfix-depleted HSPC displayed a significant loss of colony forming potential, as well as short- and long-term in vivo hematopoietic repopulating activity. Analysis of recipient mice 4-20 days post-transplant revealed that Nfix-depleted HSPC establish in the bone marrow but fail to persist due to increased apoptotic cell death. Gene expression profiling of Nfix-depleted HSPC reveals that loss of Nfix expression in HSPC is concomitant with a decrease in the expression of multiple genes known to be important for HSPC survival, such as Erg, Mecom, Mpl and Prdm16. These data reveal that Nfix is a novel regulator of HSPC survival post-transplantation and establish, for the first time, a role for Nfi genes in the regulation of this cellular compartment.

ORGANISM(S): Mus musculus

PROVIDER: GSE45492 | GEO | 2013/09/05

SECONDARY ACCESSION(S): PRJNA194388

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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Nfix is a novel regulator of murine hematopoietic stem and progenitor cell survival

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