T cell receptor repertoire in AML
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB48020 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR8980120_1.fastq.gz | Fastqsanger.gz | |||
| ERR8980120_2.fastq.gz | Fastqsanger.gz | |||
| ERR8980150_1.fastq.gz | Fastqsanger.gz | |||
| ERR8980150_2.fastq.gz | Fastqsanger.gz | |||
| ERR8980160_1.fastq.gz | Fastqsanger.gz |
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Project description:An increasing body of work reveals aberrant hypermethylation of genes occurring in and potentially contributing to the pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDS), are responsive to DNA methyltransferase inhibitors. In order to determine the extent of promoter hypermethylation in such tumors we compared the distribution of DNA methylation of 14,000 promoters in MDS and secondary AML patients enrolled in a phase I trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34+ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34+ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. Keywords: DNA methylation profiling Direct comparison of DNA methylation in bone marrow samples from patients with Myelodysplastic syndrome or secondary Acute Myeloid Leukemia (AML) at baseline and after in vivo treatment with 5-azacytidine + etinostat. A comparison to de novo normal karyotype AML was also performed. Two control groups were included: one consisting of 8 CD34+ bone marrow samples from healthy donors and a second one consisting of matched CD34+ and CD34- fractions from the bone marrows of 4 healthy donors.
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Project description:We report the application of single cell RNA and TCR sequencing technology on 22 bone marrow aspirates from 8 AML patients. By exploring 60753 AML cells and 52641 tumor microenvironment cells, we show that TCR repertoires expand and primarily emerge from CD8+ cells in responsive patients, but contract in therapy-resistant patients.Tractory analysis reveals that CD8 + T cells in AML are on continuum with GZMK expression being enriched in a memory subset of CD8 + T cells. Also, Chromosome 7/7q loss s an intrinsic AML biomarker of resistance to ICB-therapy.
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Project description:An increasing body of work reveals aberrant hypermethylation of genes occurring in and potentially contributing to the pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDS), are responsive to DNA methyltransferase inhibitors. In order to determine the extent of promoter hypermethylation in such tumors we compared the distribution of DNA methylation of 14,000 promoters in MDS and secondary AML patients enrolled in a phase I trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34+ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34+ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. Keywords: DNA methylation profiling
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Project description:The whole exome sequencing experiment is part of the study: “Analysis of 5-azacytidine resistance models reveals a set of targetable pathways”. In the study we generated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) OCI-M2 cell lines as well as patient-derived bone marrow cell lines that are resistant to hypomethylating therapy by 5-azacytidine (AZA). By integrated analysis of expression and mutation data obtained from these samples we have identified multiple signaling pathways whose modulation by specific small molecule inhibitors significantly block proliferation of AZA-resistant cell lines without increasing their sensitivity to AZA. The understanding of the molecular mechanisms which characterize the AZA-R phenotype can be used for broadening therapeutic options at progressing states during AZA therapy.
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