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

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:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-01 至 2023-05-31

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中文摘要
翻译
项目摘要 B细胞严重依赖于来自功能性B细胞受体(BCR)的连续存活和增殖信号。 同样,在约50%的B细胞恶性肿瘤中,肿瘤克隆由致癌BCR模拟物驱动。致癌 BCR依赖性增殖和存活信号的模拟物包括BCR-ABL 1(Ph+ ALL)、病毒癌蛋白(例如, EBV)、RAS和NF-κ B通路激活病变(霍奇金淋巴瘤、PMBL、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CD 25选择性地表达于 由致癌BCR模拟物驱动的恶性B细胞克隆。而CD 25作为T细胞上的IL 2受体α链, 细胞,我们最近发现CD 25是BCR信号传导和致癌BCR的关键反馈调节因子。 人B细胞肿瘤中的模拟物。遗传学实验表明,CD 25对B细胞的启动至关重要 白血病和淋巴瘤。表面表达由BTK的活性快速诱导, PKCδ位于BCR下游,并在转录水平上被FOXM 1和NF-κB诱导。CD 25招募 抑制复合物,以减少和重新校准BCR信号传导或致癌模拟 BCR信号传导。对三个临床队列的分析显示,CD 25的高表达水平与以下因素相关: 各种B细胞恶性肿瘤的临床结果较差。虽然CD 25表达与耐药性有关, 抑制CD 25或使CD 25依赖性反馈控制失效使多种B细胞恶性肿瘤对 常规药物治疗。 基于这些和其他发现,我们提出三个目标:(1)阐明CD 25调节的机制,(2) 探索CD 25介导的反馈控制的药理学颠覆的有用性和(3)靶向 通过CART 25细胞和作为治疗佐剂的抗体-药物缀合物(ADC)根除CD 25+细胞。
英文摘要
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.
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