Thyroid hormones contribute to JAK/STAT pathway abnormal activation, promoting T-cell lymphoma dissemination

Abnormal JAK/STAT pathway activation is widespread in virtually all T-cell lymphoma (TCL) subtypes. However, activating mutations are insufficient to drive leukemic cell proliferation, which also requires enhanced upstream signaling. We have described that thyroid hormones (THs) contribute to the malignant phenotype of TCL by inducing intracellular transcriptional programs through integrin αvβ3 activation. Here, we evaluate the effect of THs on the JAK/STAT pathway and its implications on TCL therapy. We found that THs induce the activation of STAT1, 3, and 5, including the upregulation of target genes and metalloprotease activity. Furthermore, we observed that the integrin αvβ3 inhibitor, cilengitide, not only reverts these effects but also enhances the antilymphoma activity to a greater extent than the JAK1/2 inhibitor, ruxolitinib, when combined with bexarotene, a synthetic rexinoid clinically used for cutaneous TCL treatment. Furthermore, we explored the mechanisms of action of cilengitide and bexarotene combination using preclinical TCL in vivo models and proteomic analysis. We found that this combinatorial protocol significantly reduced tumor STATs phosphorylation, matrix metalloproteinase activity, and the number of metastatic foci by regulating proteins involved in cell proliferation, angiogenesis, metabolism, and immune response. In addition, we observed that high integrin αvβ3 messenger RNA levels are enriched in pathways associated with lymphoma progression and reduce overall survival in samples from patients with TCL. Our findings support the therapeutic potential of targeting THs signaling through integrin αvβ3 inhibition in combination with bexarotene as a less toxic therapeutic strategy to mitigate aberrant JAK/STAT activation and limit lymphoma dissemination.