Biological and transcriptional regulation of the culprit in PDX lymphoma model

The anaplastic large cell lymphoma (ALCL), a subtype of peripheral T-cell lymphoma (PTCL), is a lymphoid malignancy characterized by a “hallmark cells” and elevated expression of CD30. Anaplastic lymphoma kinase–positive (ALK+) carry ALK fusions, more often the NPM-ALK t(2;5) translocation, while about 40% of all ALCLs are negative (ALK-). ALK chimeras promote cell survival and tumorigenesis by constitutively activating multiple cell signaling pathways, including the STAT3 pathway. STAT3 is a member of family Signal Transducers and Activators of Transcription (STATs), and its chronic activation has been proven to play a role in the pathogenesis of several PTCL malignancies. Remarkably, approximately 50% of all ALK- ALCL have been proven to display the deregulated activation of the JAK-STAT3 pathway which is required for the maintenance of their neoplastic phenotype. Here we described a series of pharmacological approaches designed to modulate the activity of STAT3 signaling. To achieve this objective, we have focused on ALK+ and ALK- ALCL cell lines and PDX models. We have taken advantage of two different but complementary molecules: a selective STAT3 binding compound named JPX-XX1, and two specific STAT3 degraders (A1 and N1). Both JPX-XX1 and A1 and N1 compounds were proven to reduce the cell growth and metabolic activity of ALK+ as well as selected ALK- ALCL cell lines, in a dose-dependent manner. As predicted both degraders were efficiently and selectively capable to degrade STAT3, a phenotype that was maintained over time (6 days of treatment) after a single dose exposure. Mechanistically, the loss of STAT3 was associated with a cell cycle arrest and increased apoptosis. Collectively our data by confirming previous findings further demonstrate the pivotal role of STAT3 signaling in ALCL. More importantly, these compounds open new and feasible therapeutic avenues for the treatment of ALCL. A strategy that may be successfully applied to other JAK/STAT3 dependent lymphoproliferative disorders.