Recurrent activating mutations of CD28 in peripheral T-cell lymphomas

J. Rohr, S. Guo, J. Huo, A. Bouska, C. Lachel, Y. Li, P. D. Simone, Weiwei Zhang, Q. Gong, C. Wang, A. Cannon, T. Heavican, A. Mottok, S. Hung, A. Rosenwald, R. Gascoyne, Kai Fu, Timothy Charles Greiner, D. D. Weisenburger, Julie Marie VoseL. M. Staudt, W. Xiao, Gloria E Borgstahl, S. Davis, C. Steidl, T. McKeithan, Javeed Iqbal, W. C. Chan

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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.

Original languageEnglish (US)
Pages (from-to)1062-1070
Number of pages9
JournalLeukemia
Volume30
Issue number5
DOIs
StatePublished - May 1 2016

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Peripheral T-Cell Lymphoma
Mutation
T-Cell Lymphoma
T-Cell Antigen Receptor
GRB2 Adaptor Protein
Ligands
T-Lymphocytes
Surface Plasmon Resonance
Epigenomics
Cell Proliferation
Cytokines
Genes
Neoplasms

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Rohr, J., Guo, S., Huo, J., Bouska, A., Lachel, C., Li, Y., ... Chan, W. C. (2016). Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia, 30(5), 1062-1070. https://doi.org/10.1038/leu.2015.357

Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. / Rohr, J.; Guo, S.; Huo, J.; Bouska, A.; Lachel, C.; Li, Y.; Simone, P. D.; Zhang, Weiwei; Gong, Q.; Wang, C.; Cannon, A.; Heavican, T.; Mottok, A.; Hung, S.; Rosenwald, A.; Gascoyne, R.; Fu, Kai; Greiner, Timothy Charles; Weisenburger, D. D.; Vose, Julie Marie; Staudt, L. M.; Xiao, W.; Borgstahl, Gloria E; Davis, S.; Steidl, C.; McKeithan, T.; Iqbal, Javeed; Chan, W. C.

In: Leukemia, Vol. 30, No. 5, 01.05.2016, p. 1062-1070.

Research output: Contribution to journalArticle

Rohr, J, Guo, S, Huo, J, Bouska, A, Lachel, C, Li, Y, Simone, PD, Zhang, W, Gong, Q, Wang, C, Cannon, A, Heavican, T, Mottok, A, Hung, S, Rosenwald, A, Gascoyne, R, Fu, K, Greiner, TC, Weisenburger, DD, Vose, JM, Staudt, LM, Xiao, W, Borgstahl, GE, Davis, S, Steidl, C, McKeithan, T, Iqbal, J & Chan, WC 2016, 'Recurrent activating mutations of CD28 in peripheral T-cell lymphomas', Leukemia, vol. 30, no. 5, pp. 1062-1070. https://doi.org/10.1038/leu.2015.357
Rohr J, Guo S, Huo J, Bouska A, Lachel C, Li Y et al. Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia. 2016 May 1;30(5):1062-1070. https://doi.org/10.1038/leu.2015.357
Rohr, J. ; Guo, S. ; Huo, J. ; Bouska, A. ; Lachel, C. ; Li, Y. ; Simone, P. D. ; Zhang, Weiwei ; Gong, Q. ; Wang, C. ; Cannon, A. ; Heavican, T. ; Mottok, A. ; Hung, S. ; Rosenwald, A. ; Gascoyne, R. ; Fu, Kai ; Greiner, Timothy Charles ; Weisenburger, D. D. ; Vose, Julie Marie ; Staudt, L. M. ; Xiao, W. ; Borgstahl, Gloria E ; Davis, S. ; Steidl, C. ; McKeithan, T. ; Iqbal, Javeed ; Chan, W. C. / Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. In: Leukemia. 2016 ; Vol. 30, No. 5. pp. 1062-1070.
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T1 - Recurrent activating mutations of CD28 in peripheral T-cell lymphomas

AU - Rohr, J.

AU - Guo, S.

AU - Huo, J.

AU - Bouska, A.

AU - Lachel, C.

AU - Li, Y.

AU - Simone, P. D.

AU - Zhang, Weiwei

AU - Gong, Q.

AU - Wang, C.

AU - Cannon, A.

AU - Heavican, T.

AU - Mottok, A.

AU - Hung, S.

AU - Rosenwald, A.

AU - Gascoyne, R.

AU - Fu, Kai

AU - Greiner, Timothy Charles

AU - Weisenburger, D. D.

AU - Vose, Julie Marie

AU - Staudt, L. M.

AU - Xiao, W.

AU - Borgstahl, Gloria E

AU - Davis, S.

AU - Steidl, C.

AU - McKeithan, T.

AU - Iqbal, Javeed

AU - Chan, W. C.

PY - 2016/5/1

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