PROJECT SUMMARY Anaplastic large cell lymphoma (ALCL) comprises a collection of mature T-cell neoplasms that share elevated expression of CD30 and anaplastic cytology. ALCL subtypes are divided into two classes based on the status of anaplastic lymphoma kinase (ALK), ALK+ and ALK-. While ALK+ ALCL is relatively homogeneous, ALK- ALCL represents a heterogeneous group comprising systemic ALK negative and primary cutaneous ALCL (pC-ALCL). The recently recognized breast implant-associated (BIA) ALCL, which arises in the seroma cavity surrounding breast implants, was acknowledged as a distinct clinical and pathological entity that shares morphologic features with ALK- ALCL. Current therapeutic strategies for ALCL are largely based on aggressive B-cell lymphoma regimens. However, the outcomes are generally much worse in patients with ALK- ALCL than in those with ALK+ ALCL. Thus, there is a need to develop novel, preferably small molecule-based targeted therapies for these lymphoid malignancies, especially in ALK- and BIA ALCL cases. A major barrier to this goal is the lack of a systematic and comprehensive understanding of the deep molecular characteristics of ALK- and BIA ALCL pathology, which is clearly needed in order to identify critical therapeutic vulnerabilities. To address the gaps in knowledge, we applied an unbiased high throughput CRISPR screening in ALCL, and identified an unexpected role of the IL-1R-MyD88 pathway in supporting ALK- and BIA ALCL. The IL-1R signaling pathway is a key mediator of immunity and inflammation and has been shown to play a critical role in many solid tumors; however, its role in lymphoid malignancies has not been established. Indeed, our preliminary studies provide the first unequivocal evidence that IL-1R1 pathway plays an essential role in supporting ALK- and BIA ALCL cell survival. Clinically, we found that IL-1 receptor and IL-1α expression are consistently elevated in primary ALK- cases, and this is correlated with IL-1R signaling activation (p-IRAK4 level) in primary samples. Moreover, using RNA-seq analysis, we identified a set of IL-1R pathway regulated genes in ALK- ALCL that overlapped significantly with signatures reflecting JAK-STAT3 activity and TH17/TH1 phenotyping. Finally, a highly specific IRAK4 inhibitor shows promising activity against ALK- and BIA ALCL in vitro and in a mouse xenograft model. Altogether, these findings provide strong support for our hypothesis that the IL-1R pathway promotes ALK- and BIA ALCL pathogenesis, and that targeting this pathway could be a novel therapeutic strategy in these diseases. In this study, we will test our hypothesis through the following aims: 1) Elucidation of the exact role of IL-1R pathway in ALK- and BIA ALCL, 2) Understanding of mechanisms regulating this pathway and its relationship to recurrent genetic lesions in ALCL, and 3) Validation of the IL-1R pathway as a novel therapeutic target in these malignancies. The proposed studies should provide critic...