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.

皮肤T细胞淋巴瘤（CTCL）是皮肤归巢性T细胞的一种不可治愈的非霍奇金淋巴瘤。在早期疾病中，病变仅限于皮肤，而在晚期疾病中，肿瘤细胞可以逃逸到血液，淋巴结甚至内脏器官中。为了阐明CTCL的基因组基础，我们对220个CTCL进行了基因组分析。我们的分析确定了55个推定的驱动基因，包括17个以前与CTCL不相关的基因。这些新的突变预计会影响染色质（BCOR，KDM6A，SMARCB1，TRRAP），免疫监视（CD58，RFXAP），MAPK信号（MAP2K1，NF1），NF-κB信号（PRKCB，CSNK1A1），PI-3-激酶信号转导（PIK3R1，VAV1），RHOA /细胞骨架重塑（ARHGEF3），RNA剪接（U2AF1），T细胞受体信号转导（PTPRN2，RLTPR）和T细胞分化（RARA） 。我们的分析确定了先前未在癌症中鉴定出的4个基因的复发突变。这些包括CK1α（由CSNK1A1编码）（p.S27F; p.S27C），PTPRN2（p.G526E），RARA（p.G303S）和RLTPR（p.Q575E）。最后，我们在功能上验证CSNK1A1和RLTPR为推定的致癌基因。RLTPR在T细胞受体信号传导途径中编码最近描述的支架蛋白。我们显示RLTPR（p.Q575E）增加了RLTPR与NF-κB信号通路下游成分的结合，选择性地上调了活化T细胞中的NF-κB通路，并最终增强了白细胞介素2的T细胞受体依赖性生产减少34倍。总的来说，我们的分析为CTCL的发病机理提供了新颖的见解，并阐明了潜在可靶向基因突变的态势。