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; pp. 1430 - 1440
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 Elsevier Inc 21-09-2017 American Society of Hematology
Subjects:	Amino Acid Sequence Amino Acid Substitution - genetics Base Sequence Genome, Human Genomics HEK293 Cells Humans Jurkat Cells Lymphoid Neoplasia 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
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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 (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. •Genomic analysis of 220 CTCLs identifies 55 genes in lymphomagenesis, including 17 genes not previously implicated in CTCL.•RLTPR (p.Q575E) is a novel gain-of-function mutation that potentiates T-cell receptor signaling via selective upregulation of the NF-κB pathway.
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood-2017-02-768234