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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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HMeDIP-sequencing of murine T-cell acute lymphoblastic leukemia (T-ALL) cells to investigate DNA hydroxymethylation profiling of lymphocyte deficient for Tet2 and mutated for DNMT3A

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive proliferation of T-lymphocytes usually associated with oncogenic activation of NOTCH1 signaling. Using a bone marrow transplantation approach, we have modeled murine CD4+ CD8+ T-ALL by overexpressing DNMT3A R882H in Tet2-/- multipotent progenitors. T-ALL derived from NOTCH1 L1601PdelP Tet2-/-, NOTCH1 L1601PdelP Tet2+/+ or TCL1A progenitors were used for comparison, as well as normal Tet2+/+ and Tet2-/- CD4+ CD8+ double positive (DP) thymocytes.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Mus musculus

SUBMITTER: Dessen Philippe

PROVIDER: E-MTAB-4161 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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MeDIP-sequencing of murine T-cell acute lymphoblastic leukemia (T-ALL) cells to investigate DNA methylation profiling of lymphocyte deficient for Tet2 and mutated for DNMT3A

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive proliferation of T-lymphocytes usually associated with oncogenic activation of NOTCH1 signaling. Using a bone marrow transplantation approach, we have modeled murine CD4+ CD8+ T-ALL by overexpressing DNMT3A R882H in Tet2-/- multipotent progenitors. T-ALL derived from NOTCH1 L1601PdelP Tet2-/-, NOTCH1 L1601PdelP Tet2+/+ or TCL1A progenitors were used for comparison, as well as normal Tet2+/+ and Tet2-/- CD4+ CD8+ double positive (DP) thymocytes.

2016-02-24 | E-MTAB-4160 | biostudies-arrayexpress

ChIP-sequencing of murine T-cell acute lymphoblastic leukemia (T-ALL) cell lines to investigate histone methylation profiling of lymphocyte deficient for Tet2 and mutated for DNMT3A

2016-02-24 | E-MTAB-4158 | biostudies-arrayexpress

RNA-sequencing of murine T-cell acute lymphoblastic leukemia (T-ALL) cells to investigate expression profiling of lymphocyte deficient for Tet2 and mutated for DNMT3A

2016-02-24 | E-MTAB-4157 | biostudies-arrayexpress

Reduced representation of bisulfite sequencing (RRBS) of murine T-cell acute lymphoblastic leukemia (T-ALL) cells to investigate DNA methylation profiling of lymphocyte deficient for Tet2 and mutated for DNMT3A

2016-02-24 | E-MTAB-4159 | biostudies-arrayexpress

Clonal hematopoiesis is driven by aberrant activation of TCL1A [ATAC-seq]

Project description:We used OMNI-ATAC to analyze the chromatin accessibility of TCL1A in TET2 edited HSPCs.

2022-12-20 | GSE205635 | GEO

5-hydroxymethylcytosine marks promoters in colon that resist hypermethylation in cancer [seq]

Project description:The discovery of cytosine hydroxymethylation (5-hmC) as a mechanism that potentially controls DNA methylation changes typical of neoplasia prompted us to investigate its behavior in colon cancer. 5-hmC is globally reduced in proliferating cells such as colon tumors and the gut crypt progenitors, from which tumors can arise. Here, we show that colorectal tumors and cancer cells express Ten-Eleven Translocation (TET) transcripts at levels similar to normal tissues. Genome-wide analyses show that promoters marked by 5-hmC in normal tissue, and those identified as TET2 targets in colorectal cancer cells, are resistant to methylation gain in cancer. In vitro studies of TET2 in cancer cells confirm that these promoters are resistant to methylation gain independently of sustained TET2 expression. We also find that a considerable number of the methylation gain-resistant promoters marked by 5-hmC in normal colon overlap with those that are marked with poised bivalent histone modifications in embryonic stem cells. Together our results indicate that promoters that acquire 5-hmC upon normal colon differentiation are innately resistant to neoplastic hypermethylation by mechanisms that do not require high levels of 5-hmC in tumors. Our study highlights the potential of cytosine modifications as biomarkers of cancerous cell proliferation. 5 normal colon samples and 4 matching tumor samples were profiled for 5-hydroxymethylcytosine content genomewide using hmeDIP-seq. The colorectal cancer cell line HCT116 was profiled for binding of TET2 genomewide by chromatin immunoprecipitation sequencing (ChIP-seq).

2015-02-03 | E-GEOD-47590 | biostudies-arrayexpress

The proto-oncogene TCL1A deregulates mitotic checkpoint transition and genomic stability in CLL

Project description:Upregulation of the proto-oncogene TCL1A is causally implicated in various B- and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, molecular and cell-biological consequences of TCL1A dysregulation are not fully elucidated. Here, we identify CDC20 and other molecules of the safeguarding cell cycle checkpoints as novel TCL1A-interactors. In different model systems of B-cell leukemia/lymphoma, TCL1A overexpression accelerated cell cycle transition, impaired apoptotic damage responses in association with pronounced chromosome mis-segregation and caused cellular aneuploidy. In primary CLL samples, low CDC20 expression correlated with high expression of TCL1A and more aggressive disease characteristics. In line, a low CDC20 expression was a marker for reduced progression-free survival in CLL patients. Finally, knockdown of CDC20 in TCL1A-initiated murine lymphomas promoted chromosome disbalances and leukemia outgrowth. Overall, we discovered a cell-cycle associated effect of TCL1A by interfering with a proficient cell cycle transition. This adds to our concept of TCL1A’s transforming impact by targeting genome stability.

2022-11-14 | PXD030776 | Pride

The proto-oncogene TCL1A deregulates mitotic checkpoint transition and genomic stability in CLL

Project description:Upregulation of the proto-oncogene TCL1A is causally implicated in various B- and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, molecular and cell-biological consequences of TCL1A dysregulation are not fully elucidated. To analyze if TCL1A’s oncogenic activity depends on its subcellular localization, we transduced murine hematopoietic stem cells and progenitor cells (HSC/HPC) with three different human TCL1A variants, being wild type, membrane-localized myristoylated (myr) TCL1A, and TCL1A fused to a nuclear localization signal (nls). All three groups developed mostly B-cell leukemias/lymphomas and less frequently CD4/CD8 double-positive or double-negative T-cell leukemia/lymphomas. Mice transplanted with cells expressing nls-hTCL1A had a significantly shorter survival in comparison to mice harboring wt TCL1A. Gene set enrichment analysis of gene expression profiling data from B-cell tumors identified nuclear pathways including DNA repair, cell cycle, and mitotic spindle to be enriched in the nls-hTCL1A over the hTCL1A cohort.

2022-11-14 | GSE192409 | GEO

Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma

Project description:DNA methylation at the 5-position of cytosine (5-mC) is a key epigenetic mark critical for varius biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the Ten-Eleven Translocation (TET) family of DNA hydroxylases. Here we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma with diagonostic and prognostic implications. Genome-wide mapping of 5-hmC in nevi and melanomas for the first time revealed loss of 5-hmC landscape in the melanoma epigenome. Downregulation of Isocitrate Dehydrogenase 2 (IDH2) and TET family enzymes proved to be one of the mechanisms underlying the loss of 5-hmC during melanoma development, and rebuilding the 5-hmC landscape in the melanoma epigenome by reintroducing active TET2 or IDH2 suppressed melanoma growth and increased tumor-free survival. Thus, our study establishes that "loss of 5-hmC" is a new epigenetic hallmark of melanoma and links IDH and TET family enzymes-mediated 5-hmC putative tumor suppressor pathway to the suppression of melanoma progression. Determine the genome-wide distribution of 5mC and 5hmC in benign nevus tissue, melanoma tissue, A2058 MOCK cells (overexpressing empty vector), A2058 TET2 cells (overexpressing wild type human TET), and A2058 TET2M cells (overexpressing mutant human TET).

2012-09-18 | E-GEOD-38231 | biostudies-arrayexpress

Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice

Project description:TET1/2/3 are methylcytosine dioxygenases regulating cytosine hydroxymethylation in the genome. Tet1 and Tet2 are abundantly expressed in HSC/HPCs and implicated in the pathogenesis of hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1 and TET2 were often concomitantly down-regulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/Tet2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2-/- HSC/HPCs had overlapping and unique 5hmC and 5mC profiles and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed onset of myeloid malignancies compared to Tet2-/- mice and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1 or TET2 individually and their cross-talks in the pathogenesis of hematological malignancies. Given the role of Tet proteins in 5mC oxidation, we employed a previously established chemical labeling and affinity purification method coupled with high-throughput sequencing (hMe-Seal) to profile the genome-wide distribution of 5hmC, as well as methylated DNA immunoprecipitation (MeDIP) coupled with high-throughput sequencing (MeDIP-seq) to profile 5mC using BM LK cells purified from young WT, Tet2-/- and DKO mice (6-10 wks old).

2015-11-12 | E-GEOD-73611 | biostudies-arrayexpress

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