Date Published: April 23, 2019
Publisher: Public Library of Science
Author(s): Rebecca L. Allchin, Michael E. Kelly, Sami Mamand, Anthony G. Doran, Thomas Keane, Matthew J. Ahearne, Simon D. Wagner, Stanislaw Stepkowski.
Recent analyses of the genetics of peripheral T-cell lymphoma (PTCL) have shown that a large proportion of cases are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain bears a mutation that increases Tfh cell number and heterozygous animals (Roquinsan/+) develop lymphomas similar to human Tfh lymphoma. Here we demonstrate the usefulness of Roquinsan/+ animals as a pre-clinical model of Tfh lymphoma. Long latency of development and incomplete penetrance in this strain suggests the lymphomas are genetically diverse. We carried out preliminary genetic characterisation by whole exome sequencing and detected tumor specific mutations in Hsp90ab1, Ccnb3 and RhoA. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and is a potential therapeutic agent. A preclinical study of ibrutinib, a small molecule inhibitor of mouse and human ITK, in established lymphoma was carried out and showed lymphoma regression in 8/12 (67%) mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice are a useful model of Tfh cell derived lymphomas in an immunocompetent animal.
Peripheral T-cell lymphomas (PTCL) are a histologically, genetically and clinically heterogeneous group of diseases. ALK+ anaplastic large cell lymphoma (ALCL) has a 5-year overall survival of ~70% but for the other common PTCL subtypes (ALK- ALCL, angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)) the clinical outlook is poor (5-year overall survival ~35%) .
There is interest in using patient derived xenograft (PDX) mouse models in order to promote the rational introduction of new therapies for PTCL . At present there are relatively small numbers of PTCL PDXs but this approach will be important for future studies. Other potential mouse models of PTCL for pre-clinical testing are deficient in Tet2, either with the RhoaG17V  or without the mutation , or bear a translocation between ITK and spleen tyrosine kinase (SYK), a chromosomal abnormality, which is found in a small minority of AITL . There is, therefore, no standard model system and yet recent advances have suggested new agents such as ITK or PI3Kδ inhibitors or anti-ICOS antibodies might be therapeutically useful . We chose to assess the usefulness of heterozygous sanroque mice as a model system for preclinical testing. The advantage of this model is that it is a source of genetically diverse primary mouse lymphomas, as suggested by the long latency of development, incomplete penetrance and confirmed by the preliminary sequencing studies presented in this report, on a background that is immunocompetent. Intriguingly we noted spontaneous regression of some enlarged lymph nodes and we wonder whether this reflects a feature of Tfh lymphomas that has been described in human disease .