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 myelodysplastic syndromes (MDSs) has been unclear. In this study, low expression of SETD2 correlated with shortened survival in patients with MDS, and the SETD2 levels in CD34+ bone marrow cells of those patients were increased by decitabine. We knocked out Setd2 in NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and found that loss of Setd2 accelerated the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhanced the ability of NHD13+ hematopoietic stem and progenitor cells (HSPCs) to self-renew, with increased symmetric self-renewal division and decreased differentiation and cell death. The growth of MDS-associated leukemia cells was inhibited though increasing the H3K36me3 level by using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulated hematopoietic stem cell signaling and downregulated myeloid differentiation pathways in the NHD13+ HSPCs. Our RNA-seq and chromatin immunoprecipitation–seq analysis indicated 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 Ikba and Jnk, which influence the self-renewal and differentiation of HSPCs. Therefore, our results demonstrated 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.

Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy

“…Thus, although KIT D816V has a central role in SM pathogenesis, it can be hypothesized that SETD2 and H3K36Me3 deficiency may cooperate with, and potentiate the effects of KIT constitutive activation to determine the phenotype of AdvSM. However, besides the pathogenetic implications, SETD2 non-genomic loss of function may turn to harbor prognostic relevance, as it has recently been observed in several solid and hematologic tumors [119][120][121][122]. In our study, in a relatively small series of patients (n = 57) there was indeed a trend towards a shorter OS in SETD2/H3K36Me3-deficient patients [109].…”

setd2 knockout zebrafish is viable and fertile: differential and developmental stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals

“…The functions of Set2/SETD2 and H3K36me3 have been implicated in various aspects of gene regulation, including transcriptional elongation [11][12][13][14]21,22 , suppression of intragenic cryptic transcription 23,24 , nucleosome dynamics 25 , DNA repair 26 , DNA methylation 27,28 , N 6 -methyladenosine (m 6 A) mRNA modification 29 , and alternative mRNA splicing 30 . Furthermore, recent human cancer genomic studies have shown that somatic mutations, deletions, and dysregulated expression of SETD2, as well as altered H3K36me3 levels, are frequently identified in many types of cancers [31][32][33][34][35] , suggesting their pivotal roles in tumorigenesis and as potential therapeutic targets.…”

Abnormal neocortex arealization and Sotos-like syndrome–associated behavior in Setd2 mutant mice

“…It has been reported that dimethylation and trimethylation at H3K36 can be recognized by DNA methyltransferase 3A (DNMT3A) and DNMT3B, respectively, suggesting that SETD2 may have a role in DNMT3A/B-mediated DNA methylation ( 43 , 44 ). Moreover, the DNA methylation profiling indicated that loss of SETD2 causes decreased CpG methylation levels in the gene body regions but increased levels in the intergenic regions ( 45 ). We thus analyzed DNMT3A and DNMT3B binding to the cPcdh enhancers and promoters in E13.5 control and Setd2 Emx1- cKO cortices using ChIP-qPCR (quantitative PCR) and observed enhanced binding of DNMT3A and DNMT3B (especially DNMT3B) to HS7L and HS5-1aL enhancers of cPcdh in Setd2 Emx1- cKO cortices.…”