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Transl. Med."],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">SETD2<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">SET domain containing 2<\/jats:italic>\n                    ) in hematopoietic stem and progenitor cells (HSPCs) from patients with MDS carrying SRSF2P95 mutations (SRSF2\n                    <jats:sup>P95-Mut<\/jats:sup>\n                    MDS) correlates with adverse outcomes and increased inflammation. Multivariate analysis confirmed the correlation between low\n                    <jats:italic toggle=\"yes\">SETD2<\/jats:italic>\n                    expression and poor prognosis in patients with SRSF2\n                    <jats:sup>P95-Mut<\/jats:sup>\n                    MDS. Furthermore, Setd2 loss in the Srsf2\n                    <jats:sup>P95H\/+<\/jats:sup>\n                    mouse model resulted in lethal MDS with hyperinflammation and expansion of myeloid-derived suppressor cells (MDSCs). Mechanistically, SETD2 methylates SRSF2\n                    <jats:sup>P95H<\/jats:sup>\n                    at lysine-17 and lysine-65 to inhibit aberrant splicing of\n                    <jats:italic toggle=\"yes\">CEACAM1-4<\/jats:italic>\n                    (isoforms of\n                    <jats:italic toggle=\"yes\">carcinoembryonic antigen cell adhesion molecule<\/jats:italic>\n                    ), which enhances interleukin-1\u03b2 (IL-1\u03b2) signaling through Slc7a11 (solute carrier family 7 member 11)\u2013mediated cystine uptake, thereby promoting HSPC differentiation into MDSCs, establishing an IL-1\u03b2\u2013driven immunosuppressive microenvironment. These findings identify the SRSF2\n                    <jats:sup>P95H<\/jats:sup>\n                    K17\n                    <jats:sup>me1<\/jats:sup>\n                    K65\n                    <jats:sup>me2<\/jats:sup>\n                    \u2013CEACAM1-4 signaling axis as a promising therapeutic target in SRSF2\n                    <jats:sup>P95-Mut<\/jats:sup>\n                    MDS.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adv1065","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:58:19Z","timestamp":1775066299000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Site-specific methylation of SRSF2\n                    <sup>P95H<\/sup>\n                    by SETD2 inhibits MDSC-mediated proinflammatory niche formation in mouse models of myelodysplastic syndrome"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5497-0235","authenticated-orcid":true,"given":"Zi-Juan","family":"Li","sequence":"first","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China."},{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0207-0016","authenticated-orcid":true,"given":"Mu-Ying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4255-6387","authenticated-orcid":true,"given":"Roujia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People\u2019s Hospital, Shanghai 200025, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-8471","authenticated-orcid":true,"given":"Na","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Institute of Hematology, Changhai Hospital, Naval Medical University, Shanghai 200433, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Long","family":"Hu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5072-7821","authenticated-orcid":true,"given":"Binhe","family":"Chang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. 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