Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of malignancies with an aggressive clinical course. Molecular and immunophenotypic analysis have linked PTCL subgroups to derivation from differentiated T cells, including T follicular helper (Tfh), Th1, and Th2 cells. Effective therapies for these PTCLs are undefined and tumor models are limited. We developed a novel mouse model of PTCL and applied it to evaluate responses to therapy. An in vivo transplantable cell line was isolated by passaging a splenic lymphoma arising from a mouse with B cell-specific Blimp1-deletion (Cγ1-Cre Blimp1fl/fl) into C57bl/6J mice. Lymphomas were profiled by flow cytometry, immunohistochemistry, RNA, and exome sequencing. Mice intravenously inoculated with lymphoma cells developed disseminated disease affecting primarily lymphoid tissues and the liver. Model latency to welfare endpoint was 3-4 weeks. Transplantable cells expressed multiple T-cell lineage markers, were CD8 negative and CD4 positive, but gradually downregulated CD4 with passaging. Lymphoma cells (“mPTCL”) also expressed a single TCRvβ chain, suggesting origin from a T helper cell clone. Immunophenotypically, mPTCL stably expressed Tfh markers ICOS, PD-1, CD40L, and low BCL6, and thus was potentially classifiable as a surrogate PTCL of Tfh phenotype. However, the transcriptome of purified mPTCL or spleens indicated a resemblance to Th2 cells and corresponding PTCL-GATA3 subtype (a PTCL-not otherwise specified). In accord with Tfh and Th2 helper function, B cells in the tumor microenvironment had an activated phenotype but were nonexpansive. Investigation into oncogenic pathways in mPTCL revealed a predicted deleterious mutation in Ctnnb1 (β-catenin) and enrichment for Myc-activated, cell cycle regulation, and DNA damage response genes. In vivo, mPTCL progression was significantly and potently delayed by monotherapy inhibition of ataxia telangiectasia and Rad3-related (ATR), a kinase central to resolving replication stress. Taken together, we established a novel model of PTCL with overlapping Tfh and Th2 features. Our findings in this model suggest the use of a DNA damage response inhibitor as a potential treatment strategy for aggressive PTCL-GATA3 lymphomas.
Citation Format: Elizabeth Kuczynski, Giulia Morlino, Alison Peter, Dinis Calado, Charles Sinclair, Larissa Carnevalli. Molecular characterization of a mouse model of peripheral T-cell lymphoma with Tfh and Th2 features [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-20.