Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE143986 | GEO | 2020/01/22
REPOSITORIES: GEO
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Project description:Adult T-cell leukemia/lymphoma (ATLL) in Japan presents at a median age of 70 years and only 5% of patients are <50 years of age. We conducted RNA and targeted DNA sequencing of 8 ATLLs from Japanese patients <50 years of age and identified 3 (37.5%) with both CTLA4-CD28 and inducible costimulator (ICOS)-CD28 fusions. Mutations of PLCG1, PRKCB, and STAT3, which were frequent in other ATLL-sequencing studies, were not identified. Differential expression analysis identified the negative checkpoint molecule LAG3 as the most downregulated gene among cases with the fusions. Immunohistochemistry demonstrated expression of CD80 and CD86, the ligands for CTLA4 and CD28, on ATLL cells and tumor-associated macrophages, respectively. Expression of CTLA4-CD28 in Ba/F3 cells conferred cytokine-independent growth when cocultured with Raji cells that express CD80 and CD86. Growth was associated with recruitment of the p85 subunit of phosphatidylinositol 3-kinase to CTLA4-CD28 and phosphorylation of AKT and extracellular signal-regulated kinase. A CTLA4-blocking antibody reduced cytokine-independent growth in a dose-dependent manner. Together, these results suggest that young Japanese ATLL cases have a unique biology dependent on cell-nonautonomous interactions that drive CD28 signaling. Assessment for CD28 fusions and treatment with CTLA4 blockade should be considered in younger patients with relapsed/refractory ATLL.
| S-EPMC7180081 | biostudies-literature
Project description:Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions
| PRJNA602442 | ENA
Project description:Previously, we have shown that an AP-1 family member Fra-2, which is hardly expressed in normal mature T cells, is consistently over-expressed in adult T-cell leukemia/lymphoma (ATLL), and together with JunD, upregulates CCR4 and many other genes including proto-oncogenes c-Myb, MDM2, Bcl-6, and SOX4. SOX4 is frequently overexpressed in many solid tumors and considered to be a potential oncogene. To identify downstream target genes of SOX4 and analyze SOX4 oncogenic pathway in ATLL , we compared gene expression profiles of ST1 cells transfected with SOX4 siRNA or control siRNA using the Affymetrix high density oligonucleotide microarray.
2013-05-16 | GSE38021 | GEO
Project description:Adult T-cell leukemia/lymphoma (ATLL) patients are in severely poor prognosis partially because of their immunosuppressive state. As majority of patients have leukemic cells with the similar phenotype with Tregs, some reports have suggested that ATLL cells themselves have immunosuppressive functions. However, hitherto, there are controvertial discussions. In this study, we found that CD39 is expressed on some of ATLL cells, especially highly on those of aggressive subtypes.
2020-04-16 | GSE127180 | GEO
Project description:BackgroundThyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality.MethodsHybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC).ResultsGAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to BRAF V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving RET, NTRK1, NTRK3, and ALK were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored RET alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in RET experienced clinical benefit from vandetanib treatment.ConclusionCGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy. The Oncologist 2017;22:255-263 IMPLICATIONS FOR PRACTICE: The detection of diverse clinically relevant genomic alterations in the majority of pediatric, adolescent, and young adult patients with thyroid carcinoma in this study suggests that comprehensive genomic profiling may be beneficial for young patients with papillary, anaplastic, or medullary thyroid carcinoma, particularly for advanced or refractory cases for which clinical trials involving molecularly targeted therapies may be appropriate.
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Project description:Previously, we have shown that an AP-1 family member Fra-2, which is hardly expressed in normal mature T cells, is consistently over-expressed in adult T-cell leukemia/lymphoma (ATLL), and together with JunD, upregulates CCR4 and many other genes including proto-oncogenes c-Myb, MDM2, Bcl-6, and SOX4. SOX4 is frequently overexpressed in many solid tumors and considered to be a potential oncogene. To identify downstream target genes of SOX4 and analyze SOX4 oncogenic pathway in ATLL , we compared gene expression profiles of ST1 cells transfected with SOX4 siRNA or control siRNA using the Affymetrix high density oligonucleotide microarray. The ATL-derived cell line ST1 was transfected with control siRNA or SOX4 siRNA using NucleofectorM-BM-. (Lonza, Basel, Switzerland). To determine the high-viability of the cells transfected with siRNAs, the cells were counted after 6 h on FACSCalibur (Becton Dickinson, Mountain View, CA) by gating out cells stained with propidium iodide. The transfection efficiency of RNAs was close to 95%, as determined by using fluorescent siRNA (Qiagen). After 48 h, total RNA samples were prepared and confirmed to be of good quality with the Agilent 2100 Bioanalyzer (Agilent Technologies, Waldbronn, Germany). In addition, quantitative PCR confirmed that SOX4 siRNA effectively reduced SOX4 mRNA in ST1 cells.
2013-05-16 | E-GEOD-38021 | biostudies-arrayexpress
Project description:Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. Recently, we and others have proposed that HTLV-1 preferentially infects CD4+CD25+CCR4+ T-cells. In this study, we used microarrays to examine the gene expression profiles of CD4+CD25+CCR4+ T-cells isolated from a HAM/TSP patient, an ATLL patient and a healthy donor to identify gene signatures that may be characteristic for these particular diseases.
2017-08-29 | GSE57259 | GEO
Project description:CTLA4-CD28 gene fusion has been reported to occur in diverse types of T-cell lymphoma. The fusion event is expected to convert inhibitory signals to activating signals promoting proliferation and potentially transformation of T-cells. To test the function of the CTLA4-CD28 fusion gene in vivo, we generated a murine model that expresses the gene in a T-cell specific manner. The transgenic mice show shorter life spans and inflammatory responses including lymphadenopathy and splenomegaly. T-cells show higher levels of activation and infiltrate various organs including skin and lung. T-cells, in particular CD4+ helper T-cells, were also readily transplanted to immunocompromised mice. Transcriptomic profiling revealed that the gene expression pattern in CD4+ cells most closely resembles that of adult T cell leukemia/lymphoma (ATLL). Consistently, we detected supernumerary Foxp3+ cells in transgenic and transplanted mice. This is the first report demonstrating the transforming activity of the CTLA4-CD28 fusion gene in vivo, and this murine model should be useful in dissecting the molecular events subsequent to the mutation in ATLL.
2022-01-01 | GSE161035 | GEO
Project description:Comparison of the genomic aberrations between periperal blood and lymph node samples with Adult T cell Leukemia/Lymphoma
2011-04-15 | E-MEXP-3042 | biostudies-arrayexpress
Project description:Transcriptional analysis of patient-derived cell lines of adult T-cell leukemia/ lymphoma (ATLL).
2022-10-01 | GSE205653 | GEO