Circulating B-Cell Chronic Lymphocytic Leukemia Cells Display Impaired Migration to Lymph Nodes and Bone Marrow
Circulating B-Cell Chronic Lymphocytic Leukemia Cells Display Impaired Migration to Lymph Nodes and Bone Marrow
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DOI：
10.1158/0008-5472.can-08-4136
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Alon, Ronen
中科院分区：
文献类型：
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作者：
Hartmann, Tanja Nicole;Grabovsky, Valentin;Alon, Ronen
归巢至次级淋巴器官和骨髓 (BM) 是白血病病理生理学的一个核心方面。我们研究了两种主要淋巴细胞整合素 LFA-1 和 VLA-4 在这些过程中对 B 细胞慢性淋巴细胞白血病 (CLL) 细胞的作用。我们发现，由于 β2 整合素转录物较低，大多数 CLL 细胞表达的 LFA-1 显着减少。 VLA-4 表达是异质的，但会被 BM 趋化因子 CXCL12 快速激活。 CLL 细胞无法迁移穿过表达 VCAM-1、表达 ICAM-1 和表达 CXCL12 的内皮细胞，而当 CLL 细胞亚群中恢复 LFA-1 表达时，这些淋巴细胞迅速迁移至内皮细胞。此外，当注射到免疫缺陷小鼠的尾静脉中时，正常 B 细胞以 LFA-1 依赖性方式迅速归巢至淋巴结 (LN)，而 CLL 细胞则不然。然而，只有残留的 CLL 子集可以重新进入 BM，而正常细胞和 CLL 细胞都以不依赖 LFA-1 和不依赖 VLA-4 的方式归巢到小鼠脾脏。我们的结果表明，CLL 细胞通过多个血管内皮床粘附和迁移的能力降低，并且很难回到脾脏以外的淋巴器官。因此，整合素阻断可能是防止循环 CLL 细胞到达 LN 和 BM 中促生存生态位的有效策略，但在脾脏中则不然。 [癌症研究 2009;69(7):3121-30]
Homing to secondary lymphoid organs and bone marrow (BM) is a central aspect of leukemic pathophysiology. We investigated the roles of the two major lymphocyte integrins LFA-1 and VLA-4 on B-cell chronic lymphocytic leukemia (CLL) cells in these processes. We found that the majority of CLL cells expressed significantly reduced LFA-1 due to low beta 2 integrin transcripts. VLA-4 expression was heterogenous but underwent rapid activation by the BM chemokine CXCL12. CLL cells failed to transmigrate across VCAM-1-expressing, ICAM-1-expressing, and CXCL12-expressing endothelium, whereas when LFA-1 expression was regained in subsets of CLL cells, these lymphocytes rapidly transmigrated the endothelium. Furthermore, when injected into tail veins of immunodeficient mice, normal B cells rapidly homed to lymph nodes (LN) in a LFA-1-dependent manner, whereas CLL cells did not. Nevertheless, only residual CLL subsets could reenter BM, whereas both normal and CLL cells homed to the mice spleen in an LFA-1-independent and VLA-4-independent manner. Our results suggest that CLL cells have a reduced capacity to adhere and transmigrate through multiple vascular endothelial beds and poorly home to lymphoid organs other than spleen. Integrin blocking could thus be an efficient strategy to prevent circulating CLL cells from reaching prosurvival niches in LNs and BM but not in spleen. [Cancer Res 2009;69(7):3121-30]