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

CD25 介导的 BCR 信号反馈控制及其致癌模拟物

• 批准号: 10339650
• 负责人: Markus Müschen
• 金额: $ 5.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339650
• 关键词: CD25; mediated; feedback; control; BCR

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.

项目概要 B 细胞严重依赖于功能性 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 BCR 模拟物驱动的。 BCR 依赖性增殖和生存信号的模拟物包括 BCR-ABL1 (Ph+ ALL)、病毒癌蛋白（例如 EBV)、RAS 和 NF-κB 通路激活病变（霍奇金淋巴瘤、PMBL、ABC-DLBCL、毛细胞 在初步研究中，我们发现 CD25 是选择性表达的。 CD25 作用于 T 上的 IL2 受体 α 链。 细胞，我们最近发现 CD25 是 BCR 信号传导和致癌 BCR-的关键反馈调节因子 基因实验证明 CD25 对于 B 细胞的启动至关重要。 BTK 和 BTK 的活性可快速诱导移植受者的白血病和淋巴瘤。 BCR 下游的 PKCδ 在转录水平上由 FOXM1 和 NF-κB 诱导，然后招募 CD25。 细胞膜的抑制复合物，可减少和重新校准 BCR 信号传导或致癌模拟 对三个临床队列的 BCR 信号分析表明，CD25 的高表达水平与相关。 各种 B 细胞恶性肿瘤的临床结果不佳，而 CD25 表达与耐药性相关。 抑制 CD25 或禁用 CD25 依赖性反馈控制可使多种 B 细胞恶性肿瘤敏感 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 调节机制，(2) 探索药理学颠覆 CD25 介导的反馈控制的有用性和 (3) 有针对性的 CART25细胞和抗体药物偶联物（ADC）作为治疗佐剂根除CD25+细胞。