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

Joonhee Park, Jingyi Yang, Alexander T. Wenzel, Akshaya Ramachandran, Wung J. Lee, Jay C. Daniels, Juhyun Kim, Estela Martinez-Escala, Nduka Amankulor, Barbara Pro, Joan Guitart, Marc L. Mendillo, Jeffrey N. Savas, Titus J. Boggon and Jaehyuk Choi

Key points

  • Genomic analysis of 220 CTCL 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 TCR signaling via selective upregulation of the NF-κB pathway.

Abstract

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 four 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). Lastly, 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 TCR-dependent production of IL-2 by 34-fold. Collectively, our analysis provides novel insights into CTCL pathogenesis and elucidates the landscape of potentially targetable gene mutations.

  • Submitted February 10, 2017.
  • Accepted June 26, 2017.