Analysis and Therapeutic Targeting of the IL-1R Pathway in Anaplastic Large Cell Lymphoma.

Anaplastic Large Cell Lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings in both ALK+ and primary cutaneous (pC) ALK- ALCLs, and identified an unexpected role of the IL-1R inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1a in an autocrine manner which is essential for the induction and maintenance of pro-tumorigenic inflammatory responses in pC ALCL cell lines and primary cases. Hyper-activation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC ALCL lines we analyzed, and is regulated by the non-proteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation, and enhances the sensitivity of JAK inhibitor in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor Pacritinib exhibited strong activities against pC ALK- ALCL where the IL-1R pathway is hyper-activated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC ALCL, and provided opportunities for developing novel therapeutic strategies.