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Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):702-714
Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
Armando N. Bastidas Torres,1 Davy Cats,2 Jacoba J. Out-Luiting,1 Daniele Fanoni,3 Hailiang Mei,2 Luigia Venegoni,3 Rein Willemze,1 Maarten H. Vermeer,1 Emilio Berti4 and Cornelis P. Tensen1
1Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands; 2Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy and 4Department of Dermatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
ABSTRACT
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lym- phoma 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 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 rele- vance 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 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 con- firmed 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 conse- quently, patients with this neoplasm would likely benefit from therapy with JAK2 inhibitors such as Food and Drug Adminstration-approved ruxolitinib.
Introduction
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma (CTCL) still regarded as a provisional entity by the World Health Organization (WHO) and characterized by an abrupt onset and a highly aggressive clinical course.1,2 pcAECyTCL presents primarily in the skin with widespread plaques and tumors, often with hemorrhagic ulcerations and necrosis; however, dissemination to extracutaneous sites (especially the central nervous system, lungs, oral cavity and testes) is not uncommon.3,4 Malignant T cells causing pcAECyTCL typically express CD3, CD7, CD8, CD45RA, TCR-βF1, T-BET and one or more cytotoxic markers (e.g., granzyme B, perforin, TIA-1), which strongly suggests that neoplastic cells in this lymphoma derive from CD8+ T cells.2,3 Effective therapeutic regimes for pcAECyTCL are cur- rently lacking, and consequently, patients have a poor prognosis with a median overall survival of 12 months.1
Thus far the study of the pathogenetic basis of this malignancy has been marginal due to its rarity. Recently, a study performed on tumors from 20 patients defined the copy number alteration (CNA) profile of pcAECyTCL by using array-based comparative genomic hybridization,5 and before this, two clinical case reports
Non-Hodgkin Lymphoma
Correspondence:
CORNELIS P. TENSEN
c.p.tensen@lumc.nl
Received: October 19, 2020. Accepted: March 24, 2021. Pre-published: April 1, 2021.
https://doi.org/10.3324/haematol.2020.274506 ©2022 Ferrata Storti Foundation
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