Site-specific methylation of SRSF2P95H by SETD2 inhibits MDSC-mediated proinflammatory niche formation in mouse models of myelodysplastic syndrome - PubMed
6 hours ago
- #inflammation
- #epigenetics
- #myelodysplastic syndrome
- Low SETD2 expression in SRSF2P95-mutant MDS patients correlates with poor prognosis and increased inflammation.
- Loss of Setd2 in a Srsf2P95H/+ mouse model leads to lethal MDS with hyperinflammation and expansion of myeloid-derived suppressor cells (MDSCs).
- SETD2 methylates SRSF2P95H at lysine-17 and lysine-65, inhibiting aberrant splicing of CEACAM1-4 isoforms.
- Aberrant CEACAM1-4 splicing enhances IL-1β signaling via Slc7a11-mediated cystine uptake, promoting HSPC differentiation into MDSCs.
- This creates an IL-1β-driven immunosuppressive microenvironment, identifying the SRSF2P95HK17me1K65me2-CEACAM1-4 axis as a therapeutic target.