title: Recurrent activating mutations of CD28 in peripheral T-cell lymphomas.
abstract: 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.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.|Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
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authors.initials: J
authors.lastname: Rohr
authors.affiliation: Department of Pathology, Xi Jing Hospital, Fourth Military Medical University, Xi'an, Shaan Xi Province, China.
authors.forename: S
authors.initials: S
authors.lastname: Guo
authors.affiliation: Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Huo
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bouska
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lachel
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Internal Medicine Residency Program, Florida Atlantic University College of Medicine, Boca Raton, FL, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Simone
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.|Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.|School of Medicine, Shandong University, Jinan, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cannon
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: T
authors.initials: T
authors.lastname: Heavican
authors.affiliation: Department for Lymphoid Cancer Research, Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Department for Lymphoid Cancer Research, Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Hung
authors.affiliation: Institute of Pathology and Comprehensive Cancer Center Mainfranken (CCC MF), University of Wuerzburg, Wuerzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department for Lymphoid Cancer Research, Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Gascoyne
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: K
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Greiner
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Weisenburger
authors.affiliation: Department of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Vose
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, Food and Drug Administration, Washington, DC, USA.
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Eppley Institute for Cancer Research and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: G E O
authors.initials: GE
authors.lastname: Borgstahl
authors.affiliation: Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Davis
authors.affiliation: Department for Lymphoid Cancer Research, Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Steidl
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: McKeithan
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
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mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D051940:B7-2 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D051940:B7-2 Antigen; D000098862:T Lineage-Specific Activation Antigen 1; D018106:CD28 Antigens; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha