Myelodysplastic Syndromes (MDSs) 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.

In a study published in Science Translational Medicine on April 1, a research team led by Dr. WANG Lan from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences, along with collaborators from other institutions, uncovered a novel mechanism underlying the formation of an immunosuppressive bone marrow niche (iBMN) in MDSs.

The researchers investigated how SET domain containing 2 (SETD2) regulates the immunosuppressive bone marrow microenvironment in MDS harboring the splicing factor serine and arginine rich splicing factor 2 (SRSF2) mutations. They found that SETD2 was expressed at low levels in hematopoietic stem and progenitor cells in MDS patients with SRSF2 mutations and was associated with poor prognosis.

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, impaired the functions of CD8⁺ T cells and natural killer T cells, and then led to the formation of iBMN, thereby accelerating MDS disease progression.

Mechanistically, the researchers found that SETD2 functioned by methylating the mutant SRSF2^P95 protein and suppressed abnormal RNA splicing caused by the mutation.

Aberrant carcinoembryonic antigen-related cell adhesion molecule 1-4 (CEACAM1-4) variants increased upon SETD2 loss, activating downstream signaling and upregulating solute carrier family 7 member 11, which led to cystine accumulation. Elevated cystine further promotes inflammatory factors such as interleukin-1β and interleukin-1 family member 9, driving the expansion of polymorphonuclear MDSCs and weakening immune responses.

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