Exome sequencing a mouse peripheral T-cell lymphoma

Peripheral T-cell lymphoma (PTCL) represents a rare group of heterogenous diseases in urgent need of effective treatments. A scarcity of disease-relevant preclinical models has considerably hindered research advances. Here, we isolated a novel mouse (m)PTCL by transplanting a lymphoma from a germinal-center B-cell hyperplasia model (C?1-Cre Blimp1fl/fl) then serially passaged it through immune-competent mice. Lymphoma cells were identified as clonal TCRß+ T-helper cells. Corresponding to a germinal-center origin, the mPTCL expressed T-follicular helper markers. Human PTCL is often associated with B-cell hyperplasia and coincident B-cell lymphomagenesis. We observed coincident B-cell activation and an example of a de novo B-cell lymphoma development in the mPTCL model. Molecular profiling further linked the mPTCL to the high-risk 'GATA3' subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway gene enrichment, hyper-activated MYC and genome instability. Exome sequencing identified a human-relevant oncogenic ß-catenin mutation possibly involved in T-cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting the DNA damage response (DDR) through ATR inhibition, a result corroborated in human PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T-cell lymphomagenesis and for the first time proposes DDR inhibition as an effective and readily translatable therapy in PTCL.