Role of Dysregulated Cytokine Signaling and Bacterial Triggers in the Pathogenesis of Cutaneous T-Cell Lymphoma

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