骨髄異形成症候群における免疫抑制環境のSETD2による制御機構（How SETD2 Regulates Immunosuppressive Bone Marrow Microenvironment in Myelodysplastic Syndromes）

2026-04-02 中国科学院（CAS）

＜関連情報＞

• https://english.cas.cn/newsroom/research-news/202604/t20260401_1154965.shtml
• https://www.science.org/doi/10.1126/scitranslmed.adv1065

SETD2によるSRSF2P95Hの部位特異的メチル化は、骨髄異形成症候群のマウスモデルにおいてMDSCを介した炎症性ニッチ形成を阻害する Site-specific methylation of SRSF2P95H by SETD2 inhibits MDSC-mediated proinflammatory niche formation in mouse models of myelodysplastic syndrome

Zi-Juan Li, Mu-Ying Zhao, Roujia Wang, Na Liu, […] , and Lan Wang
Science Translational Medicine  Published:1 Apr 2026
DOI:https://doi.org/10.1126/scitranslmed.adv1065

Editor’s summary

Myelodysplastic syndrome (MDS) is a clonal hematopoietic malignancy and has a high risk of progression to acute myeloid leukemia (AML). Here, Li et al. evaluate the underlying mechanism by which patients with SRSF2 mutations are at greater risk of MDS to AML transformation. They identify that SETD2 epigenetically inhibits mutant SRSF2 pathogenic splicing that induces an inflammatory bone marrow microenvironment that promotes MDS development. They show that targeting this signaling axis using IL-1β–neutralizing monoclonal antibody can reduce progression of MDS into leukemia in mouse models. This suggests a promising therapeutic strategy that warrants further evaluation. —Dorothy Hallberg

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 SETD2 (SET domain containing 2) 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 SETD2 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 CEACAM1-4 (isoforms of carcinoembryonic antigen cell adhesion molecule), 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.