Deregulation of JAK2 signaling underlies primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T-cell lymphoma

Abstract

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma with an aggressive clinical course and a very poor prognosis. Until now, neither a systematic characterization of genetic alterations driving pcAECyTCL has been performed, nor effective therapeutic regimes for patients have been defined. Here, we present the first high-resolution genetic characterization of pcAECyTCL by using whole-genome sequencing and RNA sequencing. Our study provides a comprehensive description of genetic alterations (i.e. genomic rearrangements, copy number alterations and small-scale mutations) with pathogenic relevance in this lymphoma, including events that recurrently impact genes with important roles in the cell cycle, chromatin regulation and the JAK-STAT pathway. In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 underlie predominantly pcAECyTCL. In line with the genomic data, transcriptome analysis uncovered up-regulation of the cell cycle, JAK2 signaling, NF-ĸB signaling and high inflammatory response in this cancer. Functional studies confirmed oncogenicity of JAK2 fusions identified in pcAECyTCL and their sensitivity to JAK inhibitor treatment. Our findings strongly suggest that overactive JAK2 signaling is a central driver of pcAECyTCL, and consequently, patients with this neoplasm would likely benefit from therapy with JAK2 inhibitors such as FDA-approved ruxolitinib.

Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers

“…Hypersensitivity of Ruxolitinib was noted in one patient with CSF3R T618I mutation, in which there were decreased white cell numbers and neutrophil counts as well as a normalization of the platelet count [103]. Effectiveness of Ruxolitinib was also seen in primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma [104], BCP-ALL [14] and ALCL [105], in which the JAK/STAT pathway played a vital role. However, whether Ruxolitinib is effective in treating PMBL remains controversial [98,99].…”

Diverse and reprogrammable mechanisms of malignant cell transformation in lymphocytes: pathogenetic insights and translational implications

“…Mutations of these two oncogenes are also frequently seen in NK and γδ T-cell lymphomas ( 37 ). In turn, cytotoxic CD8+ T-cell lymphomas of skin, particularly the primary cutaneous, aggressive and epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL) show alterations of predominantly JAK2 but also JAK3 , STAT5B, and SOCS1 genes, among other genomic changes ( 52 , 53 ). Similarly, a subset of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) was found to frequently carry mutations in STAT5B (57%), JAK3 (50%), and JAK1 (12.5%).…”

Advances in the understanding and treatment of Cutaneous T-cell Lymphoma

“…However, a deeper understanding of the genomic landscape could provide insight into potential therapeutic approaches especially in early stage disease ( 76 ). Stratification of individual patients according to mutational profile/deregulated pathway could allow the use of existing treatments such as Ipilimumab ( CD28-CTLA4 fusion), Ruxolitinib and Tofacitinib ( JAK mutations or JAK2 fusions as detected in rare aggressive cytotoxic CTCL variants) ( 77 , 78 ) and Bortezomib (NFkB pathway) ( 79 ). Patients with abnormalities of epigenetic regulation such as DNMT3A and TET2 could be selected for treatment with demethylating agents such as 5-Azactidine and/or HDACi, whilst those with RHOA mutations could be eligible for PI3K inhibitors (Duvelisib).…”