Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E)
| العنوان: | Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E) |
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| المؤلفون: | Marc L. Mendillo, Joan Guitart, Akshaya Ramachandran, Titus J. Boggon, Joonhee Park, Juhyun Kim, Jaehyuk Choi, Jay Daniels, Barbara Pro, Nduka Amankulor, Estela Martinez-Escala, Jingyi Yang, Alexander Wenzel, Jeffrey N. Savas, Wung Jae Lee |
| المصدر: | Blood. 130:1430-1440 |
| بيانات النشر: | American Society of Hematology, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Scaffold protein, T cell, Immunology, Receptors, Antigen, T-Cell, Biology, Gene mutation, medicine.disease_cause, Biochemistry, Jurkat cells, Jurkat Cells, 03 medical and health sciences, 0302 clinical medicine, Aldesleukin, medicine, Humans, Amino Acid Sequence, Mutation, Base Sequence, Genome, Human, Microfilament Proteins, NF-kappa B, Genomics, Oncogenes, Sequence Analysis, DNA, Cell Biology, Hematology, Lymphoma, T-Cell, Cutaneous, HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, Amino Acid Substitution, 030220 oncology & carcinogenesis, Cancer research, PTPRN2, Signal transduction, rhoA GTP-Binding Protein, Signal Transduction |
| الوصف: | Cutaneous T-cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing T cell. In early-stage disease, lesions are limited to the skin, but in later-stage disease, the tumor cells can escape into the blood, the lymph nodes, and at times the visceral organs. To clarify the genomic basis of CTCL, we performed genomic analysis of 220 CTCLs. Our analyses identify 55 putative driver genes, including 17 genes not previously implicated in CTCL. These novel mutations are predicted to affect chromatin (BCOR, KDM6A, SMARCB1, TRRAP), immune surveillance (CD58, RFXAP), MAPK signaling (MAP2K1, NF1), NF-κB signaling (PRKCB, CSNK1A1), PI-3-kinase signaling (PIK3R1, VAV1), RHOA/cytoskeleton remodeling (ARHGEF3), RNA splicing (U2AF1), T-cell receptor signaling (PTPRN2, RLTPR), and T-cell differentiation (RARA). Our analyses identify recurrent mutations in 4 genes not previously identified in cancer. These include CK1α (encoded by CSNK1A1) (p.S27F; p.S27C), PTPRN2 (p.G526E), RARA (p.G303S), and RLTPR (p.Q575E). Last, we functionally validate CSNK1A1 and RLTPR as putative oncogenes. RLTPR encodes a recently described scaffolding protein in the T-cell receptor signaling pathway. We show that RLTPR (p.Q575E) increases binding of RLTPR to downstream components of the NF-κB signaling pathway, selectively upregulates the NF-κB pathway in activated T cells, and ultimately augments T-cell-receptor-dependent production of interleukin 2 by 34-fold. Collectively, our analysis provides novel insights into CTCL pathogenesis and elucidates the landscape of potentially targetable gene mutations. |
| تدمد: | 1528-0020 0006-4971 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::88f3d51064de02e85a99cc75d7aea397Test https://doi.org/10.1182/blood-2017-02-768234Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....88f3d51064de02e85a99cc75d7aea397 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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