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-kB 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.

Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma / A.N. Bastidas Torres, D. Cats, J.J. Out-Luiting, D. Fanoni, H. Mei, L. Venegoni, R. Willemze, M.H. Vermeer, E. Berti, C.P. Tensen. - In: HAEMATOLOGICA. - ISSN 1592-8721. - (2021). [Epub ahead of print] [10.3324/haematol.2020.274506]

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

D. Fanoni;L. Venegoni;E. Berti;
2022

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-kB 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.
Settore MED/35 - Malattie Cutanee e Veneree
1-apr-2021
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/834404
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