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

Blood. 2017 Sep 21;130(12):1430-1440. doi: 10.1182/blood-2017-02-768234. Epub 2017 Jul 10.

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 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.

MeSH terms

  • 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
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • rhoA GTP-Binding Protein / genetics

Substances

  • CARMIL1 protein, human
  • Microfilament Proteins
  • NF-kappa B
  • Receptors, Antigen, T-Cell
  • rhoA GTP-Binding Protein