Mentor Name: Poul Sorensen

Anaplastic large cell lymphoma (ALCL) is one of the major types of T-cell lymphoma in children. Although the prognosis of ALCL has been improved in the last few decades, the commonly used chemotherapies are highly toxic and can cause gene mutations. Therefore, alternative therapeutic strategies are urgently needed, especially for growing children with cancers. One of the most promising strategies is immunotherapy (IT), which empowers a patient’s own immune system to attack cancer. We recently identified a surface protein called IL1RAP as being crucial for Ewing sarcoma cell survival and metastasis, and that it is also highly expressed in ALCL. Indeed, we recently discovered that ALK oncogene+ ALCL uniformly (100%) express IL1RAP protein, compared with ~30% frequency in ALK-neg ALCL. We have previously demonstrated that IL1RAP is directly controlled by the EWS-FLI1 and EWS-ERG fusion oncoproteins in Ewing sarcoma, and IL1RAP is minimally expressed in normal tissues except placenta, nominating IL1RAP as a promising immunotherapy target. In Ewing sarcoma, we demonstrated that IL1RAP is a crucial regulator of cysteine homeostasis, a rate-limiting substrate for antioxidant glutathione (GSH) synthesis, through interaction with the system Xc-transporter. Our data also show that when cystine is limited, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration (TSS) pathway for de novo cysteine synthesis. We hypothesize that IL1RAP is important for ALCL antioxidant homeostasis and ferroptosis defence and that it is regulated by key oncogenic drivers such as STAT3 in both ALK+ ALCL and ALK- ALCL. Preliminary data from the Sorensen lab indicate that the transcription factor STAT3 downstream of ALK signaling in ALCL, directly binds to the IL1RAP locus, and that the expression of STAT3 and IL1RAP are highly correlated in ALCL cells. In this project, we propose to decipher the regulation of IL1RAP in ALCL cells and to evaluate the impact of IL1RAP depletion on the aggressive behaviors, such as ferroptosis, in both ALK- and ALK+ ALCL cells.