Objectives
Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) is the most common mature T cell neoplasm, but its biology is hardly understood and clinical outcomes are poor. Despite the apparent morphological heterogeneity, transcriptional clustering delineates only two major subgroups characterized by their differential expression of TBX21 and GATA3. Differential expression of these lineage-specifying transcription factors, suggests different cellular origins and driver mutations. These have not been studied before. We propose an integrated genomic study to identify driver mutations in these transcriptionally distinct diseases. A first objective is to obtain an integrated genomic characterization of PTCL, NOS by mapping the mutational and the transcriptional landscape in diagnostic samples. This will allow us to correlate specific mutations with alterations in signal transduction pathways. A second objective is to validate the transforming potential of these mutations and co-operation between these mutations in vitro. We will prioritize actionable mutations. A third objective is to establish relevant mouse models. The fourth objective is to validate the therapeutic potential of our findings by targeting actionable mutations and activated pathways in representative mouse models.

Methods
Next-generation sequencing (NGS), bio-informatics, cell culture, CRISPR-Cas9 gene editing, patient-derived xenografts, bone marrow transplant model, preclinical drug studies

Results
The first 20 samples are in final preparation for NGS (DNA, RNA). We want to collect 60-70 samples.

Conclusion
We aim to identify therapeutic vulnerabilities in PTCL, NOS and will prioritize genetic events that are targetable with available compounds for further study. Current guidelines recommend to treat patients with PTCL, NOS in the context of a clinical trial due to the paucity of effective treatment options. This project has the potential to instigate new clinical trials in PTCL, NOS.

The identification of actionable genetic events driving disease progression and heterogeneity in peripheral T cell lymphoma, not otherwise specified