EMBO Mol Med - 2022 - Kuczynski - A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response (2).pdf (3.85 MB)
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A preclinical model of peripheral T-cell lymphoma GATA3 reveals DNA damage response pathway vulnerability.

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journal contribution
posted on 09.06.2022, 10:49 authored by Elizabeth A Kuczynski, Giulia Morlino, Alison Peter, Anna ML Coenen-Stass, Jennifer I Moss, Neha Wali, Oona Delpuech, Avinash Reddy, Anisha Solanki, Charles Sinclair, Dinis P Calado, Larissa S Carnevalli
Peripheral T-cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease-relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B-cell hyperplasia model (Cγ1-Cre Blimp1fl/fl ) through immune-competent mice. Lymphoma cells were identified as clonal TCRβ+ T-helper cells expressing T-follicular helper markers. We also observed coincident B-cell activation and development of a de novo B-cell lymphoma in the model, reminiscent of B-cell activation/lymphomagenesis found in human PTCL. Molecular profiling linked the mPTCL to the high-risk "GATA3" subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway enrichment, hyperactivated MYC, and genome instability. Exome sequencing identified a human-relevant oncogenic β-catenin mutation possibly involved in T-cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting ATR in the DNA damage response (DDR), a result corroborated in PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T-cell lymphomagenesis and proposes DDR inhibition as an effective and readily translatable therapy in PTCL.

Funding

Crick (Grant ID: 10057, Grant title: Calado FC001057) Medical Research Council (Grant ID: MR/J008060/1, Grant title: MRC MR/J008060/1)

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