Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany.
CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Center for Molecular Medicine Cologne, Cologne, Germany.
Leukemia. 2022 Jul;36(7):1794-1805. doi: 10.1038/s41375-022-01586-1. Epub 2022 May 6.
The scaffold protein NEDD9 is frequently upregulated and hyperphosphorylated in cancers, and is associated with poor clinical outcome. NEDD9 promotes B-cell adhesion, migration and chemotaxis, pivotal processes for malignant development. We show that global or B-cell-specific deletion of Nedd9 in chronic lymphocytic leukemia (CLL) mouse models delayed CLL development, markedly reduced disease burden and resulted in significant survival benefit. NEDD9 was required for efficient CLL cell homing, chemotaxis, migration and adhesion. In CLL patients, peripheral NEDD9 expression was associated with adhesion and migration signatures as well as leukocyte count. Additionally, CLL lymph nodes frequently expressed high NEDD9 levels, with a subset of patients showing NEDD9 expression enriched in the CLL proliferation centers. Blocking activity of prominent NEDD9 effectors, including AURKA and HDAC6, effectively reduced CLL cell migration and chemotaxis. Collectively, our study provides evidence for a functional role of NEDD9 in CLL pathogenesis that involves intrinsic defects in adhesion, migration and homing.
支架蛋白 NEDD9 在癌症中经常上调和过度磷酸化，与不良的临床结局相关。NEDD9 促进 B 细胞黏附、迁移和趋化，这是恶性发展的关键过程。我们发现，在慢性淋巴细胞白血病（CLL）小鼠模型中，Nedd9 的全局或 B 细胞特异性缺失延迟了 CLL 的发展，显著降低了疾病负担，并带来了显著的生存获益。NEDD9 是 CLL 细胞归巢、趋化、迁移和黏附的必需条件。在 CLL 患者中，外周 NEDD9 表达与黏附和迁移特征以及白细胞计数相关。此外，CLL 淋巴结经常表达高水平的 NEDD9，其中一部分患者的 CLL 增殖中心富集了 NEDD9 表达。阻断显著的 NEDD9 效应物（包括 AURKA 和 HDAC6）的活性，可有效减少 CLL 细胞的迁移和趋化。总之，我们的研究为 NEDD9 在 CLL 发病机制中的功能作用提供了证据，该作用涉及黏附、迁移和归巢的内在缺陷。
