Myelodysplastic Syndromes (MDS) are a group of blood disorders characterized by ineffective blood cell production and a high risk of progression to leukemia. Increasing evidence suggests that changes in the bone marrow microenvironment play a critical role in disease development, but the underlying mechanisms remain incompletely understood.

On April 1, 2026, the group led by Dr. WANG Lan at the Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences, in collaboration with multiple institutions, uncovered a novel mechanism underlying the formation of an immunosuppressive bone marrow niche (iBMN) in myelodysplastic syndromes, entitled “Site specific methylation of SRSF2^P95Hby SETD2 inhibits MDSCs-mediated proinflammatory niche formation in mouse models of myelodysplastic syndrome”, and was published in Science Translational Medicine.

This study investigats how SETD2 (SET domain containing 2) regulates the bone marrow immunosuppressive environment in myelodysplastic syndrome (MDS) harboring the splicing factor SRSF2 (serine and arginine rich splicing factor 2) mutations.

Using the mouse model, the researchers revealed that the loss of SETD2 promoted the expansion of myeloid-derived suppressor cells (MDSCs) in Srsf2^P95H/+ mice, and impaired the functions of CD8⁺ T cells and natural killer T cells, then led to the formation of iBMN, thereby accelerating MDS disease progression.

Mechanistically, researchers found that SETD2 functions by methylating the mutant SRSF2^P95 protein and suppresses abnormal RNA splicing caused by the mutation. Aberrant CEACAM1-4 (carcinoembryonic antigen-related cell adhesion molecule 1-4) variants increase upon SETD2 loss, activating downstream signaling and upregulating SLC7A11 (solute carrier family 7 member 11), which leads to cystine accumulation. Elevated cystine further promotes inflammatory factors such as interleukin-1β (IL-1β) and interleukin-1 family member 9 (IL1F9), driving the expansion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and weakening immune responses.

This work uncovered the mechanism of SETD2 functions in the MDSCs expansion, and the formation of iBMN in MDS patients with SRSF2 mutations, revealed the disease-promoting role of CEACAM1-4. Importantly, this work proposes a potential therapeutic strategy for MDS patients harboring the SRSF2 mutations by targeting the CEACAM1-4/IL-1β axis.

This study was co-first authored by Dr. LI Zijuan (postdoctoral fellow) and ZHAO Muying (Ph.D. candidate) from SINH; Dr. WANG Roujia from Shanghai Sixth People’s Hospital, l, Shanghai Jiao Tong University School of Medicine; and Dr. LIU Na (assistant researcher) from the First Affiliated Hospital of Naval Medical University.

The corresponding authors are Dr. WANG Lan from SINH; Dr. SUN Xiaojian from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Dr. CHANG Chunkang from Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine; and Dr. HE Pengcheng from the First Affiliated Hospital of Xi’an Jiaotong University.

This work was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, etc.

The authors would like to thank Academicians CHEN Zhu and CHEN Saijuan for their guidance, and also thank Dr. LIANG Yang from the Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, and Prof. LIU Yan from the Department of Medicine, Northwestern University Feinberg School of Medicine for their strong support.

Mechanisms and therapeutic targeting strategies of SETD2 in regulating the formation of the immunosuppressive microenvironment in myelodysplastic syndrome. (Image provided by Dr. WANG Lan’s group)

Paper link: https://doi.org/10.1126/scitranslmed.adv1065

Scientific Contact:
Dr. WANG Lan
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: lwang@sinh.ac.cn

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn