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Methylation of SRSF2P95H by SETD2 suppresses myeloid-derived suppressor cell function by inhibiting inflammatory signaling in myelodysplastic syndrome

ABSTRACT: Myelodysplastic syndrome (MDS) is a malignant hematologic cancer accompanied with ineffective hematopoietic and myeloid bias. MDS patients with the SRSF2 mutation have a poor prognosis and require specific and effective therapeutic agents. Here, we find that the low expression of SETD2 in the SRSF2P95H background is associated with anomalously increased myeloid derived suppressor cells (MDSCs) differentiation and inflammatory response. Our results reveal that the low expression of SETD2 in the hematopoietic stem and progenitor cells (HSPCs) of MDS patients with SRSF2P95H/+ is associated with patient outcomes. The deletion of Setd2 in Srsf2P95H/+ mice led to lethal MDS in mice, and mechanistic studies showed that Setd2 catalyzing the K17me1 and K65me2 methylation modification of Srsf2P95H/+ protein, to inhibit the aberrant expression of Ceacam1-4 isoforms and inhibit the increased differentiation potential of HSPCs into MDSCs and the formation of Il-1β-related inhibitory tumor microenvironment. Overall, our findings proposed the possibility of targeting the CEACAM1-4- IL-1β signaling axis in the clinical treatment of SRSF2P95H/+ MDS patients

ORGANISM(S): Mus musculus

PROVIDER: GSE265871 | GEO | 2025/10/24

REPOSITORIES: GEO

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Project description:Mutations in spliceosomal genes are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations occur at highly restricted amino acid residues and perturb normal splice site and exon recognition. Spliceosomal mutations are always heterozygous and rarely co-occur with one another, suggesting that cells may only tolerate a partial deviation from normal splicing activity. To test this hypothesis, we generated mice with inducible hemizygous expression of the commonly occurring SRSF2P95H mutation in the hematopoietic system. These mice rapidly developed lethal bone marrow failure upon activation of the Srsf2P95H mutation with concomitant deletion of the wildtype Srsf2 allele, demonstrating that Srsf2-mutant cells depend on the wildtype Srsf2 allele for survival. We next tested whether spliceosomal-mutant leukemias display greater sensitivity to pharmacologic splicing inhibition induced by the small molecule E7107. Treatment of isogenic murine leukemias as well as patient-derived xenograft (PDX) AMLs showed significant reductions in leukemic burden specifically in samples carrying spliceosomal mutations. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal mutations are preferentially susceptible to additional splicing perturbations in vivo compared with wildtype counterparts. Modulation of spliceosome function may provide a novel therapeutic avenue in genetically defined subsets of MDS/AML patients. We created an isogenic murine leukemia model by retroviral overexpression of the MLL-AF9 fusion oncogene in Vav-Cre Srsf2+/+ or Vav-Cre Srsf2P95H/+ BM cells followed by transplantation into lethally irradiated recipient mice. In order to determine the mechanistic origins of the Srsf2 mutant-selective effects of E7107, we analyzed transcriptional changes after five consecutive days of E7107 or vehicle treatment in vivo. GFP+ Cd11b+ cells were purified from the BM of recipient mice exactly three hours after the last dose of E7107 and were subjected to paired-end 2x50bp RNA-seq. For the knock-in/knock-out experiments, we generated inducible, hemizygous Srsf2P95H mice to study the effects of wildtype Srsf2 deletion with concomitant activation of the Srsf2P95H allele. Mx1-cre Srsf2fl/+ mice were crossed to Srsf2P95H/+ mice to generate Srsf2 wildtype (Mx1-cre Srsf2+/+), Srsf2 heterozygous knockout (Mx1-Cre Srsf2+/-), Srsf2 heterozygous P95H mutant (Mx1-Cre Srsf2P95H/+), and Srsf2 hemizygous P95H mutant (Mx1-Cre Srsf2P95H/-) mice, which were subjected to single-end 101bp RNA-seq.

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Methylation of SRSF2P95H by SETD2 suppresses myeloid-derived suppressor cell function by inhibiting inflammatory signaling in myelodysplastic syndrome

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