Genetic drivers of peripheral T-cell lymphomagenesis

Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of neoplasms derived from post-thymic mature T cells. With few exceptions, outcome is poor with an average 5-year overall survival of 30 to 40%. Up to 25% of patients have primary refractory disease and an additional 50% will relapse after first-line treatment. Thus, PTCL represents an unmet medical need.

These poor outcomes necessitate new treatment strategies, but several obstacles impede their rational design. Only recently, advances in sequencing technologies facilitated the detetection of genomic events in PTCL. Nevertheless, due to the heterogeneity of PTCL and the rarity of individual entities we still lack unbiased, genome-scale sequencing studies on a sufficient number of cases for certain subtypes. In addition, diligent functional validation of genomic events is trailing behind due to the paucity of representative cell models and challenges to model PTCL in mice.

In this thesis, I performed unbiased genome-scale next-generation sequencing (NGS) assays to identify recurrent somatic events in PTCL and I established cell models and mouse models to study the pathogenicity of selected mutations. This analysis reaffirmed previously identified driver mutations and identified recurrent, previously unreported disease variants. I focused on the biological activity of new gene fusions in PTCL which originated from this analysis. Gene fusions are recurrent disease drivers in various hematologic malignancies. Gene fusions often define a specific disease entity and may confer therapeutic vulnerability.

I identified gene fusions involving the FES tyrosine kinase family members FES and FER in follicular T-cell lymphoma (FTCL). Despite the central role of STAT3 in T follicular helper cells, the contribution of STAT3 to FTCL remains obscure. We demonstrate activation of STAT3 in the majority of FTCL. ITK::FER and RLTPR::FES fusion proteins contribute to STAT3 activation in FTCL.

In the same cohort, I identified a FYN::TRAF3IP2 gene fusion in 10-15% of cases and an isolated KHDRBS1::LCK gene fusion. The FYN::TRAF3IP2 fusion protein instigates a highly penetrant PTCL in mice. It acts as a constitutively active E3 ubiquitin ligase and signaling adaptor with canonical NF-κB signaling as its chief executor. NF-κB-dependent induction of anti-apoptotic proteins engenders therapeutic vulnerability in FYN::TRAF3IP2-driven PTCL.

Collectively, this thesis describes novel gene fusions in PTCL and provides insights in their biological activity which provide a framework for new treatment regimens.