Setd2 deficiency impaired erythroid differentiation and accelerated Myelodysplastic Syndrome(MDS) - associated leukemogenesis through S100A8 and S100A9

Setd2, the histone H3 lysine 36 methyltransferase, plays an important role in the pathogenesis of hematologic malignancies. The research on the role of Setd2 in leukemogenesis has made great progress, but its role in MDS is still unknown. Here, we knock out Setd2 in the NUP98-HOXD13 transgenic (NHD13 Tg) mouse, and demonstrate that loss of Setd2 accelerates the transformation of MDS into AML. The conditional deletion of Setd2 also interferes the differentiation of hematopoietic stem and progenitor cells (HSPCs), and results in the decrease of granulocyte monocyte progenitor (GMP) cells, increase of megakaryocyte erythroid progenitor (MEP) cells and common myeloid progenitor (CMP) cells. Loss of Setd2 impairs erythroid differentiation, includes cell cycle arrest in G2-M and enhances the selt-renewal ability of HSPCS. Our RNA-seq,ChIP-seq and WGBS analysis indicats that S100A8 and S100A9 are direct target genes of H3K36me3 and expression of heterodimeric S100 calcium-binding proteins S100A8 and S100A9 are downregulated in HSPCs when Setd2 deficiency. Addition of recombinant S100A8 or S100A9 weakens the clonogenic progenitors of Setd2 deficient HSPCs. Therefore, our results demonstrate that loss of Setd2 promotes the transformation of MDS into AML, which proves Setd2 as a tumor suppressor in MDS, and provides a potential therapeutic target for MDS associated leukemia. Overall design: We used Mx1-Cre-induced deletion of Setd2 in Nup98-HoxD13 (NHD13) transgenic mice. C-Kit+ cells were sorted from spleen cells in NHD13 and NHD13_Setd2 KO mice at leukemia stage (NHD13 - AML and NHD13/Setd2 KO - AML), and ChIP-seq was performed with an anti-H3K36me3 antibody. Hematopoietic stem and progenitor cells (HSPCs) were sorted from bone marrow (BM) cells in C57BL/6, NHD13/Setd2 flox/flox and NHD13/Setd2 KO mice, and C-Kit+ cells were sorted from spleen cells in NHD13/Setd2 KO - AML, and these cells were subjected to RNA-seq analysis and WGBS.