PloS one, 2019-04-23, Vol.14 (4), p.e0215765-e0215765
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 (Roquin(san/+)) develop lymphomas similar to human Tfh lymphoma. Here we demonstrate the usefulness of Roquin(san/+) 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.
Administration, Oral ; Animals ; Antineoplastic Agents - administration & dosage ; Cell death ; Disease Models, Animal ; Drug Evaluation, Preclinical - methods ; Drug therapy ; Heterozygote ; Humans ; Lymph Nodes - cytology ; Lymph Nodes - diagnostic imaging ; Lymph Nodes - drug effects ; Lymphoma, T-Cell, Peripheral - diagnostic imaging ; Lymphoma, T-Cell, Peripheral - drug therapy ; Lymphoma, T-Cell, Peripheral - genetics ; Magnetic Resonance Imaging ; Mice ; Multidisciplinary Sciences ; Non-Hodgkin's lymphomas ; Primary Cell Culture ; Prognosis ; Pyrazoles - administration & dosage ; Pyrimidines - administration & dosage ; Research ; Science & Technology ; Science & Technology - Other Topics ; T cells ; T-Lymphocytes, Helper-Inducer - drug effects ; T-Lymphocytes, Helper-Inducer - pathology ; Treatment Outcome ; Tumor Cells, Cultured ; Ubiquitin-Protein Ligases - genetics ; Usage
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