CD25-mediated feedback control of BCR-signaling and its oncogenic mimics

项目总结 B细胞在很大程度上依赖于功能正常的B细胞受体(BCR)的持续存活和增殖信号。 同样，在大约50%的B细胞恶性肿瘤中，肿瘤克隆是由致癌的BCR模拟物驱动的。致癌作用 BCR依赖的增殖和生存信号的模拟物包括BCR-ABL1(Ph+ALL)、病毒癌蛋白(例如：BCR-ABL1)、BCR-ABL1(Ph+ALL)和BCR-ABL1。 EB病毒)、RAS和NF-κB途径激活性病变(霍奇金淋巴瘤、粒细胞淋巴瘤、ABC-DLBCL、毛细胞 白血病、Waldenström巨球蛋白血症)。在初步研究中，我们发现CD25被选择性地表达 致癌BCR-模拟物驱动的恶性B细胞克隆的研究而CD25在T细胞上作为IL_2受体α链发挥作用 细胞，我们最近发现CD25是bcr信号和致癌bcr的关键反馈调节因子。 在人类B细胞肿瘤中模拟。遗传学实验证明CD25在B细胞的启动中起关键作用 移植受者的白血病和淋巴瘤。BTK和BTK的活性可快速诱导细胞表面表达 PKCδ位于bcr下游，在转录水平上受FOXM1和NF-κB诱导。CD25然后招募 一种对细胞膜的抑制复合体，以减少和重新校准bcr信号或致癌模拟 BCR-信令。对三个临床队列的分析表明，CD25的高表达水平与 各种B细胞恶性肿瘤的临床转归较差。虽然CD25的表达与耐药性有关， 抑制CD25或禁用CD25依赖的反馈控制使多种B细胞恶性肿瘤对 常规药物治疗。 基于这些和其他发现，我们提出了三个目标：(1)阐明CD25的调控机制；(2) 探索药物颠覆CD25介导的反馈控制的有用性和(3)有针对性 CART25细胞和抗体-药物结合物(ADC)作为治疗佐剂清除CD25+细胞。

PROJECT SUMMARY B cells critically depend on continuous survival and proliferation signals from a functional B cell receptor (BCR). Likewise, in ~50% of B cell malignancies, the tumor clone is driven by an oncogenic BCR-mimic. Oncogenic mimics of BCR-dependent proliferation and survival signals include BCR-ABL1 (Ph+ ALL), viral oncoproteins (e.g. EBV), RAS- and NF-κB-pathway activating lesions (Hodgkin's lymphoma, PMBL, ABC-DLBCL, hairy cell leukemia, Waldenström's macroglobulinemia). In preliminary studies, we found that CD25 is selectively expressed on malignant B cell clones driven by oncogenic BCR-mimics. While CD25 functions as IL2 receptor α-chain on T cells, we recently discovered that CD25 is a critical feedback regulator of BCR signaling and oncogenic BCR- mimics in human B cell tumors. Genetic experiments demonstrated that CD25 is critical for the initiation of B cell leukemia and lymphoma in transplant recipients. Surface expression is rapidly induced by activity of BTK and PKCδ downstream of the BCR and induced by FOXM1 and NF-κB at the transcriptional level. CD25 then recruits an inhibitory complex to the cell membrane to reduce and recalibrate BCR signaling or oncogenic mimicry of BCR-signaling. Analysis of three clinical cohorts revealed that high expression levels of CD25 are associated with poor clinical outcome in various B cell malignancies. While CD25 expression is associated with drug-resistance, inhibition of CD25 or disabling of CD25-dependent feedback control sensitizes multiple B cell malignancies to conventional drug-treatment. Based on these and other findings, we propose three Aims to (1) elucidate mechanisms of CD25 regulation, (2) explore usefulness of pharmacological subversion of CD25-mediated feedback control and (3) targeted eradication of CD25+ cells by CART25 cells and antibody-drug conjugates (ADC) as therapeutic adjuvant.