Site-specific methylation of SRSF2^P95H by SETD2 inhibits MDSC-mediated proinflammatory niche formation in mouse models of myelodysplastic syndrome.

Abstract

Patients with myelodysplastic syndrome (MDS) harboring SRSF2 (serine and arginine rich splicing factor 2) mutations exhibit poor prognosis and aberrant inflammatory activation, underscoring an urgent need for therapies. Here, we reveal that low messenger RNA expression of <i>SETD2</i> (<i>SET domain containing 2</i>) in hematopoietic stem and progenitor cells (HSPCs) from patients with MDS carrying SRSF2P95 mutations (SRSF2^P95-Mut MDS) correlates with adverse outcomes and increased inflammation. Multivariate analysis confirmed the correlation between low <i>SETD2</i> expression and poor prognosis in patients with SRSF2^P95-Mut MDS. Furthermore, Setd2 loss in the Srsf2^P95H/+ mouse model resulted in lethal MDS with hyperinflammation and expansion of myeloid-derived suppressor cells (MDSCs). Mechanistically, SETD2 methylates SRSF2^P95H at lysine-17 and lysine-65 to inhibit aberrant splicing of <i>CEACAM1-4</i> (isoforms of <i>carcinoembryonic antigen cell adhesion molecule</i>), which enhances interleukin-1β (IL-1β) signaling through Slc7a11 (solute carrier family 7 member 11)-mediated cystine uptake, thereby promoting HSPC differentiation into MDSCs, establishing an IL-1β-driven immunosuppressive microenvironment. These findings identify the SRSF2^P95HK17^me1K65^me2-CEACAM1-4 signaling axis as a promising therapeutic target in SRSF2^P95-Mut MDS.