SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS

Abstract

SETD2, the histone H3 lysine 36 methyltransferase previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in MDS has been unclear. In this study, we show that low expression of SETD2 correlates with shortened survival in MDS patients and that the SETD2 levels in CD34⁺ bone marrow (BM) cells of MDS patients can be increased by decitabine. We knock out Setd2 in the NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and demonstrate that loss of Setd2 accelerates the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhances the ability of NHD13⁺ HSPCs to self-renew, with increased symmetric self-renewal division and decreased differentiation/cell death. The growth of MDS-associated leukemia cells can be inhibited though increasing H3K36me3 level by using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulates hematopoietic stem cell (HSC) signaling and downregulates myeloid differentiation pathways in the NHD13⁺ HSPCs. Our RNA-seq and ChIP-seq analysis indicate that S100a9, the S100 calcium-binding protein, is a target gene of Setd2 and that the addition of recombinant S100a9 weakens the effect of Setd2 deficiency in the NHD13⁺ HSPCs. In contrast, downregulation of S100a9 leads to decreases of its downstream targets, including IƙBα and Jnk, which influence the self-renewal and differentiation of HSPCs. Therefore, our results demonstrate that SETD2 deficiency predicts poor prognosis in MDS and promotes the transformation of MDS into AML, which provides a potential therapeutic target for MDS-associated acute leukemia.