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

• We elucidate the molecular mechanism by which thyroid hormones contribute to the aberrant activation of JAK/STAT pathway in TCL.

• We demonstrate that cilengitide in combination with bexarotene decreases tumor metalloprotease activity and TCL dissemination

Abnormal JAK/STAT pathway activation is widespread in virtually all T cell lymphomas (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 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 anti-lymphoma activity to a greater extent than the JAK1/2 inhibitor, ruxolitinib, when combined with bexarotene, a synthetic rexinoid clinically used for cutaneous TCL treatment. Additionally, 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, MMPs activity, and the number of metastatic foci by regulating proteins involved in cell proliferation, angiogenesis, metabolism, and immune response. Additionally, we observed that high integrin αvβ3 mRNA levels are enriched in pathways associated with lymphoma progression and reduce overall survival in TCL patient samples. 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