Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E)

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 b...

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Published in:Blood Vol. 130; no. 12; p. 1430
Main Authors: Park, Joonhee, Yang, Jingyi, Wenzel, Alexander T, Ramachandran, Akshaya, Lee, Wung J, Daniels, Jay C, Kim, Juhyun, Martinez-Escala, Estela, Amankulor, Nduka, Pro, Barbara, Guitart, Joan, Mendillo, Marc L, Savas, Jeffrey N, Boggon, Titus J, Choi, Jaehyuk
Format: Journal Article
Language:English
Published: United States 21.09.2017
Subjects:
Amino Acid Sequence
Amino Acid Substitution - genetics
Base Sequence
Genome, Human
Genomics
HEK293 Cells
Humans
Jurkat Cells
Lymphoma, T-Cell, Cutaneous - genetics
Microfilament Proteins - chemistry
Microfilament Proteins - genetics
Mutation - genetics
NF-kappa B - metabolism
Oncogenes
Receptors, Antigen, T-Cell - metabolism
rhoA GTP-Binding Protein - genetics
Sequence Analysis, DNA
Signal Transduction - genetics
ISSN:1528-0020, 1528-0020
Online Access:Get more information
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Summary: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 ( , , , ), immune surveillance ( , ), MAPK signaling ( , ), NF-κB signaling ( , ), PI-3-kinase signaling ( , ), RHOA/cytoskeleton remodeling ( ), RNA splicing ( ), T-cell receptor signaling ( , ), and T-cell differentiation ( ). Our analyses identify recurrent mutations in 4 genes not previously identified in cancer. These include CK1α (encoded by ) (p.S27F; p.S27C), PTPRN2 (p.G526E), RARA (p.G303S), and RLTPR (p.Q575E). Last, we functionally validate and as putative oncogenes. 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.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2017-02-768234