VLA-4 整合素通过 BCR 自主信号传导在循环慢性淋巴细胞白血病细胞中具有组成型活性：一种利用可溶性血源性配体的新型锚独立机制。
The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands.
发表日期：2024 Aug 14
作者：
Erika Tissino, Annalisa Gaglio, Antonella Nicolò, Federico Pozzo, Tamara Bittolo, Francesca Maria Rossi, Riccardo Bomben, Paola Nanni, Ilaria Cattarossi, Eva Zaina, Anna Maria Zimbo, Giulia Ianna, Guido Capasso, Gabriela Forestieri, Riccardo Moia, Moumita Datta, Andrea Härzschel, Jacopo Olivieri, Giovanni D'Arena, Luca Laurenti, Francesco Zaja, Annalisa Chiarenza, Giuseppe A Palumbo, Enrica Antonia Martino, Massimo Gentile, Davide Rossi, Gianluca Gaidano, Giovanni Del Poeta, Roberta Laureana, Maria Ilaria Del Principe, Palash C Maity, Hassan Jumaa, Tanja Nicole Hartmann, Antonella Zucchetto, Valter Gattei
来源：
Experimental Hematology & Oncology
摘要：
在慢性淋巴细胞白血病 (CLL) 中，肿瘤细胞的存活取决于淋巴部位的微环境信号，其中约 40% 的 CLL 中表达的整合素 VLA-4 (CD49d/CD29) 与 B 细胞受体 (BCR) 之间的串扰）发生。在这里，BCR 由内而外的参与激活了 VLA-4，从而增强了 VLA-4 介导的 CLL 细胞粘附，进而从周围微环境中获得促生存信号。我们报告说，BCR 还能够通过自主抗原独立的 BCR 信号传导，有效地从内到外激活循环表达 CD49d 的 CLL 细胞中的 VLA-4 整合素。因此，表现出激活的 VLA-4 的循环 CLL 细胞表达 BCR 途径激活的标记物（磷酸化 BTK 和磷酸化 PLC-γ2）以及较高水平的磷酸化 ERK 和磷酸化 AKT，表明下游途径平行激活。此外，表达活化VLA-4的循环CLL细胞结合可溶性血源性VCAM-1，导致VLA-4依赖性肌动蛋白聚合/重组和ERK磷酸化增加。最后，有证据表明，依鲁替尼治疗通过影响自主 BCR 信号传导，损害 VLA-4 的组成型激活，最终减少可溶性 VCAM-1 结合并减少循环 CLL 细胞的下游 ERK 磷酸化。这项研究描述了循环 CLL 细胞中发生的一种新颖的锚独立机制，涉及 BCR 和 VLA-4 整合素，这有助于揭示 CD49d CLL 的独特生物学和临床特征。© 2024。作者。
In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside-out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside-out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling. As a consequence, circulating CLL cells exhibiting activated VLA-4 express markers of BCR pathway activation (phospho-BTK and phospho-PLC-γ2) along with higher levels of phospho-ERK and phospho-AKT indicating parallel activation of downstream pathways. Moreover, circulating CLL cells expressing activated VLA-4 bind soluble blood-borne VCAM-1 leading to increased VLA-4-dependent actin polymerization/re-organization and ERK phosphorylation. Finally, evidence is provided that ibrutinib treatment, by affecting autonomous BCR signaling, impairs the constitutive VLA-4 activation eventually decreasing soluble VCAM-1 binding and reducing downstream ERK phosphorylation by circulating CLL cells. This study describes a novel anchor-independent mechanism occurring in circulating CLL cells involving the BCR and the VLA-4 integrin, which help to unravel the peculiar biological and clinical features of CD49d+ CLL.© 2024. The Author(s).