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DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS

ABSTRACT: DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS

PROVIDER: PRJNA842653 | ENA |

REPOSITORIES: ENA

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DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS [RNA-Seq]

Project description:Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall-survival, with DNMT3A mutated residues skewed towards the methyltransferase domain and dimerization motif (S881–R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genome-wide methylation analysis of DNMT3A-mutant versus wild-type PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating IFN-g, TCR signaling and EOMES, a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in-vivo) and further validated in-vitro by ectopic expression of DNMT3A-mutants (DNMT3A-R882, -Q886, -V716, versus WT) in CD8+T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A-mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T-cells with DNMT3AR882H mutation. Single-cell-RNA-seq analysis of CD3+ T-cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance, thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

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DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS [meDIP-Seq]

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DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS [meDIP-Seq]

Project description:DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS [meDIP-Seq]

| PRJNA842660 | ENA

DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS [RNA-Seq]

Project description:DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS [RNA-Seq]

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SNP array genomic profiling of PTCL NOS

Project description:DNA extracted from frozen tissue of 47 peripheral T-cell lymphomasânot otherwise specified [PTCL-NOS] was hybridized to 250k StyI SNP arrays 47 PTCL NOS compared to healthy reference DNA. DNA of PTCL NOS was extracted from frozen tissue blocks, DNA of healthy individual was extracted from peripheral blood mononuclear cells. Array hybridization was performed according to manufacturerÂ´s protocol.

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SNP array genomic profiling of PTCL NOS

Project description:DNA extracted from frozen tissue of 47 peripheral T-cell lymphomas–not otherwise specified [PTCL-NOS] was hybridized to 250k StyI SNP arrays

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RNA sequencing of PTCL-NOS

Project description:To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we performed RNA-sequencing of 15 cases. We describe a recurrent FYN-TRAF3IP2 fusion transcript in PTCL-NOS and PTCL-TFH and a KHDRBS1-LCK fusion transcript in PTCL-NOS.

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DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T-cells in PTCL-NOS

Project description:This SuperSeries is composed of the SubSeries listed below.

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