B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406
B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406
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DOI：
10.1182/blood-2009-03-212837
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发表时间：
2009-07-30
期刊：
影响因子：
20.3
通讯作者：
Burger, Jan A.
中科院分区：
文献类型：
--
作者：
Quiroga, Maite P.;Balakrishnan, Kumudha;Burger, Jan A.
通过B细胞抗原受体（BCR）的抗原刺激被认为可以促进慢性淋巴细胞白血病（CLL） B细胞的扩张。脾酪氨酸激酶（Syk）是BCR信号的关键组成部分，可被R406阻断，R406是一种小分子Syk抑制剂，在CLL患者中首次临床试验显示出活性。在这项研究中，我们研究了BCR刺激和R406对CLL细胞存活和迁移的影响。抗igm刺激和乳样细胞的促存活作用被R406所消除。BCR触发上调粘附分子，并增加CLL细胞向趋化因子CXCL12和CXCL13迁移。BCR激活也增强了CLL细胞在骨髓基质细胞下的迁移。这些反应被R406阻断，R406进一步消除了CLL细胞依赖bcr分泌的t细胞趋化因子（CCL3和CCL4）。最后，R406抑制构成型和bcr诱导的Syk、细胞外信号调节激酶和AKT的激活，并阻断bcr诱导的钙动员。这些发现表明BCR激活有利于CLL细胞在组织微环境中的归巢、滞留和存活。R406有效地阻断了CLL细胞中bcr依赖性的反应，这为R406在CLL患者中的活性提供了解释。[血液。2009;114:1029-1037]
Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL. (Blood. 2009; 114: 1029-1037)