Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of Cutaneous T Cell Lymphoma.

4 years ago

Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of Cutaneous T Cell Lymphoma.

Niels Ødum, Adriana Heguy, Laura K Fogli, Rodrigo S Lacruz, Mary E Laird, Igor Dolgalev, Jeff Kutok, Vijay Narendran, Swati Goel, Melania H Fanok, Mark S Sundrud, Amy Sun, Kenneth B Hymes, Iannis Aifantis, Cynthia Liu, Jo-Ann Latkowski, Charalampos Lazaris, Kasthuri Kannan, Miriam Eckstein, Sergei B Koralov

Cutaneous T cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome revealed a highly heterogeneous landscape of genetic perturbations and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway, previously implicated in CTCL pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of CTCL. Using this mouse model, we demonstrate that T cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.

Publisher URL: http://doi.org/10.1016/j.jid.2017.10.028

DOI: 10.1016/j.jid.2017.10.028