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. 2019 Sep;104(9):e388-e392.
doi: 10.3324/haematol.2018.214155. Epub 2019 Mar 7.

Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling

Daniel A Pollyea  1 , Chelsea Harris  2   3 , Jennifer L Rabe  1 , Brenna R Hedin  2   3 , Lesly De Arras  3 , Sigrid Katz  4 , Emily Wheeler  4 , Rafael Bejar  4 , Matthew J Walter  5 , Craig T Jordan  1 , Eric M Pietras  1 , Scott Alper  6   3   7
Affiliations

Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling

Daniel A Pollyea et al. Haematologica. 2019 Sep.
No abstract available

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Figures

Figure 1.
Figure 1.
Spliceosome gene mutations found in myelodysplastic syndrome (MDS) patients enhance innate immunity signaling in macrophages. (A) siRNA targeting the indicated spliceosome genes or a control non-targeting siRNA were transfected into RAW264.7 mouse macrophages, the cells were then stimulated with 20 ng/mL lipopolysaccharide (LPS) for 6 hours (h), and IL-6 protein production was monitored by ELISA. (B-G) Plasmids expressing the indicated wild-type (WT) (black) or mutant (red) spliceosome genes were co-transfected into RAW264.7 cells along with either an IL-6 luciferase reporter construct (B-D) or an NFκB-dependent luciferase reporter construct (E-G) and a SV40-rluc construct for normalization. The cells were then stimulated with 20 ng/mL LPS for 6 h, and luciferase activity was monitored. Data represent mean, Standard Error of Mean. *P<0.05. If no P-value is indicated, the comparison was not significantly different.
Figure 2.
Figure 2.
Spliceosome gene mutations found in myelodysplastic syndrome (MDS) patients enhance inflammatory cytokine production in cancer-relevant myeloid cells. (A-I) Cytokine mRNA levels were assayed in K562 cells carrying the indicated spliceosome gene mutations (red) or wild-type (WT) control genes (black). (J) IL-6 mRNA was analyzed in lipopolysaccharide (LPS)-induced (20 ng/mL LPS for 4 hours) peripheral blood monocytes isolated from MDS patients either carrying mutations in spliceosome genes (all splice, n=8, 3 SF3B1, 3 SRSF2, 2 U2AF1, color-coded red) or not carrying mutations in these three spliceosome genes (WT, color-coded black). Patient demographics are described in the Online Supplementary Table S1. (K-P) IL-6 mRNA was analyzed in the indicated myeloid cell types from mice engineered to express either WT human U2AF1 (black) or U2AF1-S34F (red). Data represent mean, Standard Error of Mean. *P<0.05. If no P-value is indicated, the comparison was not significantly different.
Figure 3.
Figure 3.
Myelodysplastic syndrome (MDS)-associated spliceosome gene mutations alter splicing of genes that regulate innate immune signaling. The indicated mRNA isoforms were monitored by isoform-specific quantitative polymerase chain reaction on RNA isolated from K562 cells carrying the indicated spliceosome gene mutations (red) or wild-type (WT) control genes (black). MAP3K7 alt refers to the alternative isoform of MAP3K7 that uses an alternate 3’ splice site in intron 4. CASP8Δ6 refers to the alternate CASP8 isoform in which exon 6 is skipped. Data represent mean, Standard Error of Mean. *P<0.05. If no P-value is indicated, the comparison was not significantly different.
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References

    1. Scott LM, Rebel VI. Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors. J Natl Cancer Inst. 2013;105(20):1540–1549. - PubMed
    1. De Arras L, Alper S. Limiting of the innate immune response by SF3A-dependent control of MyD88 alternative mRNA splicing. PLoS Genet. 2013;9(10):e1003855. - PMC - PubMed
    1. De Arras L, Laws R, Leach SM, et al. Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity. Genetics. 2014;197(2):485–496. - PMC - PubMed
    1. De Arras L, Seng A, Lackford B, et al. An evolutionarily conserved innate immunity protein interaction network. J Biol Chem. 2013;288(3):1967–1978. - PMC - PubMed
    1. O’Connor BP, Danhorn T, De Arras L, et al. Regulation of toll-like receptor signaling by the SF3a mRNA splicing complex. PLoS Genet. 2015;11(2):e1004932. - PMC - PubMed

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