Age-related epigenetic drift in the pathogenesis of MDS and AML part 2
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Yue Lu
PROVIDER: E-GEOD-46065 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Genomic DNA is isolated from bone marrow (MDS patient) and whole blood (normal control). We used MCAM to identify genes that have methylation changes. Two-condition experiment, MDS patient vs. normal control.
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Project description:Genomic DNA is isolated from spleen (RUNX1 model and normal control) and bone marrow (NHD13 model and normal control). We used MCAM to identify genes that have methylation changes.
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Project description:Genomic DNA is isolated from bone marrow (MDS patient) and whole blood (normal control). We used MCAM to identify genes that have methylation changes.
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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.
2022-10-12 | GSE213530 | GEO
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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Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. To determine the molecular mechanism of severe cytopenia in NHD13+ Tg mice, we purified Lin-Sca-1+c-Kit+CD34-Flt3-CD150+ HSCs from WT and NHD13+Tg mice at 4 month of age and perform the RNA-seq analysis. Methods: Trizol was used to extract RNA from FACS sorted CD150+CD34–Flt3–LSK viable cells. Total RNA was used for quality controls and for normalization of starting material. cDNA-libraries were generated with 10 ng of total RNA using the SMARTer Ultra Low RNA Kit for Illumina Sequencing according to the manufacturer’s indications. Sequencing was done using the Illumina Next-Gen Sequencing HiSeq platform with 30-45 million 75bp, paired-end reads. Results: We found 597 genes with significantly differential expression in NHD13+ HSCs, compared to WT controls (p<0.001). The expression of NUP98-HOXD13 up-regulated the expression of HOX genes, including Hoxa3, Hoxa5, Hoxa7, Hoxa9, Hoxb6, Hoxc5, Hoxc6, Hoxc8, Hoxc9 and Hoxd3, the important myeloid transcription factor Pbx3, cell cycle regulators, Cdk6 and Cdc25C, as well as the transcripts encoding the Ly6d surface membrane protein. We then performed pathway analyses, which showed that DNA duplication, DNA damage response and cell cycle-related genes, were more highly expressed in NHD13+ HSCs than WT HSCs, while multiple metabolic process-related gene pathways were downregulated. Conclusions: Our analyses demonstrate that the gene expression signature defined in murine NHD13+ MDS HSCs displays robust similarities with the gene expression profiles of human MDS cells, strongly suggesting that this murine MDS model can be used to accurately model human MDS.
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Project description:The myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylation in the bone marrow and spleen in two mouse models of MDS/AML, the NUP98-HOXD13 (NHD13) mouse and the RUNX1 mutant mouse model. Methylation array analysis showed an average of 512/3445 (14.9%) genes hypermethylated in NHD13 MDS, and 331 (9.6%) genes hypermethylated in RUNX1 MDS. Thirty-two percent of genes in common between the two models (2/3 NHD13 mice and 2/3 RUNX1 mice) were also hypermethylated in at least two of 19 human MDS samples. Detailed analysis of 41 genes in mice showed progressive drift in DNA methylation from young to old normal bone marrow and spleen; to MDS, where we detected accelerated age-related methylation; and finally to AML, which markedly extends DNA methylation abnormalities. Most of these genes showed similar patterns in human MDS and AML. Repeat element hypomethylation was rare in MDS but marked the transition to AML in some cases. Our data show consistency in patterns of aberrant DNA methylation in human and mouse MDS and suggest that epigenetically, MDS displays an accelerated aging phenotype.
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Project description:Analysis of Lin-c-Kit+Sca-1- haematopoietic stem cells (HSCs) expressing the Nup98-HoxD13 (NHD13) fusion gene. NHD13 induces myelodysplastic syndrome (MDS) in mice. Results provide insight into the molecular basis of the myelodysplastic phenotype WT mouse HSCs were compared to an NHD13 mutant sequenced in triplicate on a HiSeq 2000
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Project description:To identify the mechanism by which miRNAs in EVs derived from MDS cells suppressed the osteolineage differentiation of MSCs and disrupted normal hematopoiesis, we comprehensively explored the miRNAs encapsulated in EVs by miRNA-array. Consistent with the heterogeneous nature of MDS, the hypoplastic Abcg2-MDS/AML model and the hyperplastic NHD13Tg model share few elevated miRNAs. However, it is noteworthy that the pathways targeted by each upregulated miRNA are mutually shared, such as the pathways associated with MSC differentiation and survival, including axon guidance and MAPK signaling. These results suggest that miRNAs play an essential role in the MSC impairment observed in MDS.
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