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Abstract 2983: CD25 enables oncogenic BCR- and TCR-signaling and represents a therapeutic target in lymphoblastic malignancies

B- and T-cells critically depend on survival and proliferation signals from a functional B-cell (BCR) or T-cell receptor (TCR). In >50%, tumor clones are driven by oncogenic B/TCR-mimics, e.g. mutant B/TCR-signaling chains (Igβ, CD3ζ), BCR-ABL1, viral oncoproteins (e.g. EBV; KSHV, HTLV-I) and NF-κB-pathway lesions. Despite this heterogeneity, our correlative analyses showed that oncogenic B/TCR signaling in lymphoid malignancies is uniformly characterized by high surface levels of CD25. CD25 is known as α-chain of the IL2 receptor. Our results revealed an unrecognized function as essential feedback regulator of oncogenic B/TCR-signaling. In adults (MDACC, ECOG) and children (COG; P9906) with Ph-like or Ph+ ALL, high surface levels of CD25 predict particularly poor outcome (n=416; P=0.005). While CD25 mediates IL2 signaling in T cells, CD25 on B- cells was not responsive to IL2. Our studies showed that oncogenic B/TCR-signaling rapidly induced surface translocation of CD25 by PKCδ-dependent phosphorylation (S268) and transcriptional activation by NF-κB. Engagement of CD25 induced recruitment of an inhibitory phosphatase complex (SHIP1, PP2A) at the cell membrane to limit kinase signaling (e.g. SYK, SRC and ERK) downstream of the B/TCR or its oncogenic mimics. Consistent with a role as negative feedback regulator, genetic deletion of CD25 in B cells caused uncoordinated Ca2+ oscillations, p53 checkpoint activation and cell cycle arrest. In leukemia models, CD25-/- cells failed to initiate fatal disease in transplant recipients, which could be rescued by expression of the CD25 cytoplasmic tail. Depending on PKCδ-mediated phosphorylation at S268, CD25 shuttles between cytoplasm and cell membrane. Mirroring cellular activation states, only a fraction of tumor cells express CD25 on the surface at any given time, while pharmacological activation of PKCδ (I3A) forced continuous surface expression. As strategy to eradicate CD25-expressing B- and T-cell malignancies, we combined PKCδ-activation by I3A with a CD25-antibody drug conjugate (ADCT-301) to treat NSG mice xenografted with patient-derived Ph+ ALL cells. While ADCT-301 induced durable remissions alone, combinations of I3A and ADCT-301 eradicated disease with NSG mice surviving for indefinite periods of time. In conclusion, we identified the IL2Rα chain CD25 as a previously unrecognized feedback regulator of oncogenic B/TCR-signaling and as a therapeutic target in refractory lymphoid malignancies. Citation Format: Jaewoong Lee, Huimin Geng, Zhengshan Chen, Gang Xiao, Kadriye Nehir Cosgun, Francesca Zammarchi, Patrick Van Berkel, Ari Melnick, Elisabeth Paietta, Markus Muschen. CD25 enables oncogenic BCR- and TCR-signaling and represents a therapeutic target in lymphoblastic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2983.