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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE129691 | GEO | 2020/07/02

REPOSITORIES: GEO

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ROBO1 deficiency impairs hematopoietic stem progenitor cell self-renewal and erythropoiesis via CDC42 and predicts poor prognosis in MDS

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Induction of S100A8/S100A9 mediates the erythroid differentiation block in ribosomal protein S14 haploinsufficiency

Project description:Schneider RK, Schenone M, Kramann R, Ferreira MV, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Gehrming U, Platzbecker U, Buesche G, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Nat Med, 2016. Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100A8/S100A9 proteins in purified erythroblasts. S100A8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100A8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS.

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

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

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Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML (RNA-Seq)

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TET2 deficiency promotes MDS-associated leukemogenesis

Project description:Loss of function TET2 mutations are frequently seen in myelodysplastic syndrome (MDS) patients. Previous studies have demonstrated that TET2 deficiency enhances maintenance of MDS hematopoietic stem and progenitor cells (HSPCs). Nonetheless, the pathogenic role of TET2 in MDS progression remains elusive. Here, we demonstrate Tet2 knockout (KO) markedly accelerated malignant transformation in Nup98-HoxD13 (NHD13) transgenic mice and promotes leukemogenesis of HoxA9 transduction/transplant mice. Consistently, low TET2 level cooperating with high HOXA9 level predicts poor outcome of MDS patients. Notably, Tet2 KO conferred a clonal advantage to the HSPCs of NHD13 mice. Whole-exome sequencing revealed that Tet2 KO facilitates accumulation of mutations at genes associated with leukemogenesis, including Arih2, whose loss of function promotes MDS cells proliferation. Using 5-hydroxymethylcytosine immunoprecipitation coupled with high-throughput sequencing analysis, we found while Tet2 deletion decreased overall 5hmC levels, it also increased 5hmC distribution at certain mutation loci such as Arih2. Vitamin C treatment, which mimics Tet2/Tet3 restoration, blocked disease progression in Tet2-deficient NHD13 mice. Collectively, our findings demonstrate that TET2 activity governs occurrence of secondary mutations in MDS HSPCs, providing a rationale for enhancing TETs function to block MDS-malignant transformation.

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TET2 deficiency promotes MDS-associated leukemogenesis

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MLL-PTD and RUNX1-knockout cooperate to induce MDS phenotypes

Project description:The MLL-PTD mutation is found in patients with MDS and AML, and not in other hematological malignancies. Previously, we showed that Mll-PTD knock-in heterozygous mice (MllPTD/WT mice) present with several MDS-associated features. However, these phenotypes are insufficient to constitute bona fide MDS. MllPTD/WT mice do not generate MDS or AML in primary or transplant recipient mice. This suggests that additional genetic and/or epigenetic defects are necessary for transformation to MDS or AML. In secondary AML and de novo AML, MLL-PTD mutation is significantly associated with mutations in RUNX1 and with the FLT3-ITD mutations. In fact, the combination of MLL-PTD with the FLT3-ITD allele leads to AML in mice. We combined the MLL-PTD with RUNX1 mutant proteins, in order to generate a new mouse model for MDS. We generated MllPTD/WT/Runx1Flox/Flox/Mx1-Cre mice to model loss-of-function RUNX1 mutations. To test the significance of HIF-1α in this model, we also generated MllPTD/WT/Runx1Flox/Flox/Hif-1αFlox/Flox/Mx1-Cre mice and genetically eliminated Hif-1α expression. We analyzed gene expression variations in the HSPCs comparing the MllPTD/WT/Runx1∆/∆ with or without HIF-1α abrogation.

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S100A8 treatment on gene expression of human umbilical vascular endothelial cells.

Project description:Previous studies showed that S100A8 and S100A9 are involved in neovascularization as well as in tumor development. At high concentrations, S100A8 and S100A9 cause inflammatory response or apoptosis mediated damage in vascular endothelial cells. But the effect of low concentrations of such proteins on endothelial cells remains unknown. This assay was performed to screen for genes that are involved in the response of Human Unbilican Vascular Endothelial Cells to low concentrations of S100A8. Human Umblical Vascular Endothelial Cells (HUVEC) were cultuered and treated with 10ug/mL S100A8 proteins for 4 or 24 hours. Gene profiling was carried out using two-color microarray. Two-condition experiment, S100A8 treatment vs. non-treatment. Two time points: 4 hours and 24 hours. Biological replicates at each time point: 3 control replicates, 3 treatment replicates.

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