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

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