| Autor: |
Bastidas Torres AN; Department of Dermatology, Leiden University Medical Center, Leiden., Cats D; Sequencing Analysis Support Core, Leiden University Medical Center, Leiden., Out-Luiting JJ; Department of Dermatology, Leiden University Medical Center, Leiden., Fanoni D; Department of Pathophysiology and Transplantation, University of Milan, Milan., Mei H; Sequencing Analysis Support Core, Leiden University Medical Center, Leiden., Venegoni L; Department of Pathophysiology and Transplantation, University of Milan, Milan., Willemze R; Department of Dermatology, Leiden University Medical Center, Leiden., Vermeer MH; Department of Dermatology, Leiden University Medical Center, Leiden., Berti E; Department of Dermatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan., Tensen CP; Department of Dermatology, Leiden University Medical Center, Leiden. c.p.tensen@lumc.nl. |
| Abstrakt: |
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 highresolution genetic characterization of pcAECyTCL by using wholegenome 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 JAKSTAT pathway. In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL. In line with the genomic data, transcriptome analysis uncovered upregulation of the cell cycle, JAK2 signaling, NF-κB signaling and a 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 Food and Drug Adminstration-approved ruxolitinib. |
