通过 BCR 自主信号传导,VLA-4 整合素在循环慢性淋巴细胞白血病细胞中持续活跃:一种利用可溶性血源性配体的新型锚依赖机制

IF 12.8 1区 医学 Q1 HEMATOLOGY
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
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引用次数: 0

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,在这些部位,整合素 VLA-4(CD49d/CD29)与 B 细胞受体(BCR)之间会发生串联。在这里,BCR 从内向外参与激活了 VLA-4,从而增强了 VLA-4 介导的 CLL 细胞粘附,而 CLL 细胞又从周围微环境中获得了促生存信号。我们报告说,BCR 还能通过独立于抗原的 BCR 信号转导,有效地从内向外激活循环中表达 CD49d 的 CLL 细胞中的 VLA-4 整合素。因此,表现出活化的 VLA-4 的循环 CLL 细胞会表达 BCR 通路活化的标记物(磷酸化-BTK 和磷酸化-PLC-γ2)以及更高水平的磷酸化-ERK 和磷酸化-AKT,这表明下游通路被同时活化。此外,表达活化的 VLA-4 的循环 CLL 细胞会与可溶性血载 VCAM-1 结合,导致依赖 VLA-4 的肌动蛋白聚合/重组和 ERK 磷酸化增加。最后,研究提供的证据表明,伊布替尼治疗通过影响自主BCR信号传导,损害了组成型VLA-4活化,最终减少了可溶性VCAM-1的结合,降低了循环CLL细胞下游的ERK磷酸化。这项研究描述了循环CLL细胞中发生的一种新型锚依赖机制,涉及BCR和VLA-4整合素,有助于揭示CD49d+ CLL的特殊生物学和临床特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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

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
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.
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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