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. 2017 Feb;31(2):491-495.
doi: 10.1038/leu.2016.276. Epub 2016 Oct 3.

Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome

M E Varney  1 , K Choi  1 , L Bolanos  1 , S Christie  1 , J Fang  1 , H L Grimes  2 , J P Maciejewski  3 , J-I Inoue  4 , D T Starczynowski  1   5
Affiliations

Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome

M E Varney et al. Leukemia. 2017 Feb.

Erratum in

No abstract available

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Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Combined deletion of Tifab and miR-146a, neighboring del(5q) MDS genes, results in a BM failure. (a) Schematic representation showing the genomic position of the TIFAB locus at chr 5q31.1 and miR-146a locus at chr 5q33.3. The syntenic mouse regions corresponding to human chr 5q31.1 and 5q33.3 are shown below. (b) Model of TRAF6 regulation by miR-146a and TIFAB as previously reported: miR-146a suppresses TRAF6 mRNA and translation., TIFAB suppresses TRAF6 protein stability. Immunoblotting of BM cells from mice transplanted with WT, Tifab−/−, miR-146a−/−, or Tifab−/−; miR-146a−/− (dKO) BM cells. Representative image from two independent transplantation experiments. Densitometric values for TRAF6 protein are shown below the image. (c) BM isolated from control (WT), Tifab−/−, miR-146a-/and Tifab−/−; miR-146a−/− (dKO) mice was transplanted into lethally-irradiated syngeneic recipient BoyJ mice. PB counts were performed at the indicated time points (months; n>8 per group) from two independent transplants. PLT, platelet; RBC, red blood cell; WBC, white blood cell;. (d) PB counts from mice transplanted with WT, Tifab−/−, miR-146a−/− and Tifab−/−; miR-146a−/− (dKO) at 6 months post transplant (n>8 per group). Error bars are mean ± s.e.m. values. (e) Kaplan–Meier survival curves for transplanted mice reconstituted with BM cells from WT (n=7), Tifab−/− (n=7), miR-146a−/− (n=6) and Tifab−/−; miR-146a−/− (dKO; n =10) mice. (f) PB counts from age-matched WT (n=5) or moribund dKO (n = 8) mice. PLT, platelet; RBC, red blood cell; WBC, white blood cell. (g) H&E-stained spleen, BM (femur), liver, lung and kidney, and Wright-Giemsa-stained PB from a representative moribund dKO mouse. *P<0.05; Student's t test.
Figure 2
Figure 2
Differential expression and score of synergy genes in Tifab−/−;miR-146a−/− HSPC cells and co-regulation in human del(5q) MDS. (a) Heat map showing gene expression differences (fold-change >2.0; FDR <0.05) in LK isolated from 5-month-old mice transplanted with WT, Tifab−/−, miR-146a−/− and Tifab−/−; miR-146a−/− (dKO) BM cells (n=3 mice/group). The heat map shows log2 fold-changes as compared with WT. The color boxes represent genes predominantly expressed in dKO (green), miR-146a−/− (blue) or Tifab−/− (orange) cells. (b) Pathway analysis generated from differentially expressed genes in Tifab−/− vs WT (orange), miR-146a−/− vs WT (blue), and dKO vs WT (green) comparisons. Shown are the highest relevant enriched pathways generated by Toppgene. (c) Bar graphs ranking synergy scores calculated from genes in Tifab−/− vs WT, miR-146a−/− vs WT, and dKO vs WT comparisons. (d) Pathway and network analysis generated from synergy genes in dKO using Netwalker. Colored nodes represent synergy genes. Gray nodes indicate molecularly connected genes. (e) Unsupervised hierarchical clustering and heat map showing expression differences of the synergy genes from MDS CD34+ BM cells (n=183). The heat map was generated using normalized expression values. (f) Three patients examined by single-nucleotide polymorphism array have shorter telomeric breakpoints, which include deletion of TIFAB (5q31), but not miR-146a (5q33.3). Six patients have longer telomeric breakpoints, which include deletion of TIFAB and miR-146a. Heat map showing expression differences of the synergy genes from 9 MDS and AML patient BM mononuclear cells. The heat map was generated using Z-scores. The bar graph represents fold change (FC; log2) generated from M-values comparing expression of individual genes from patients with the long deletion versus the short deletion. *P <0.05; Student's t test.
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References

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