Recurrent activating mutations of CD28 in peripheral T-cell lymphomas
| Autor: | J Huo, Andreas Rosenwald, Christian Steidl, Kai Fu, Gloria E. O. Borgstahl, Randy D. Gascoyne, Qiang Gong, D. D. Weisenburger, Louis M. Staudt, Timothy C. Greiner, Yuping Li, Simon J. Davis, Joseph Rohr, Peter D. Simone, Andrew Cannon, Shuangping Guo, Anja Mottok, Wenming Xiao, Weiwei Zhang, Cynthia M. Lachel, Alyssa Bouska, Julie M. Vose, Tayla Heavican, Stacy Hung, Javeed Iqbal, Timothy W. McKeithan, Chao Wang, Wing C. Chan |
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| Rok vydání: | 2015 |
| Předmět: |
Antigens
Differentiation T-Lymphocyte Models Molecular 0301 basic medicine Cancer Research RHOA CD3 T cell Article Fusion gene 03 medical and health sciences CD28 Antigens medicine Humans CD86 biology Tumor Necrosis Factor-alpha NF-kappa B Lymphoma T-Cell Peripheral CD28 Hematology Surface Plasmon Resonance medicine.disease Lymphoma Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Oncology Mutation biology.protein Cancer research B7-2 Antigen GRB2 Protein Binding |
| Zdroj: | Leukemia. 30:1062-1070 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2015.357 |
| Popis: | Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T-cell neoplasms with a poor prognosis. Recently, mutations in TET2 and other epigenetic modifiers as well as RHOA have been identified in these diseases, particularly in angioimmunoblastic T-cell lymphoma (AITL). CD28 is the major co-stimulatory receptor in T-cells which, upon binding ligand, induces sustained T-cell proliferation and cytokine production when combined with T-cell receptor stimulation. We have identified recurrent mutations in CD28 in PTCLs. Two residues – D124 and T195 – were recurrently mutated in 11.3% of cases of AITL and in one case of PTCL, not otherwise specified (PTCL-NOS). Surface plasmon resonance analysis of mutations at these residues with predicted differential partner interactions showed increased affinity for ligand CD86 (residue D124) and increased affinity for intracellular adaptor proteins GRB2 and GADS/GRAP2 (residue T195). Molecular modeling studies on each of these mutations suggested how these mutants result in increased affinities. We found increased transcription of the CD28-responsive genes CD226 and TNFA in cells expressing the T195P mutant in response to CD3 and CD86 co-stimulation and increased downstream activation of NF-κB by both D124V and T195P mutants, suggesting a potential therapeutic target in CD28-mutated PTCLs. |
| Databáze: | OpenAIRE |
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