Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease.
Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease.
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DOI：
10.1002/ajh.23433
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发表时间：
2013-06
影响因子：
12.8
通讯作者：
Yaccoby, Shmuel
中科院分区：
文献类型：
--
作者：
Bam, Rakesh;Ling, Wen;Khan, Sharmin;Pennisi, Angela;Venkateshaiah, Sathisha Upparahalli;Li, Xin;van Rhee, Frits;Usmani, Saad;Barlogie, Bart;Shaughnessy, John;Epstein, Joshua;Yaccoby, Shmuel
骨髓瘤细胞通常生长在骨中，招募破骨细胞前体，并在肿瘤灶附近区域诱导其分化和活性。Bruton氏酪氨酸激酶(BTK)属于TEC家族，在造血细胞中表达，尤其参与B淋巴细胞功能和破骨细胞的形成。我们研究了BTK在临床骨髓瘤浆细胞、白介素6或基质依赖细胞系和破骨细胞中的表达。SDF-1诱导骨髓瘤细胞BTK活化，小发夹RNA或小分子抑制剂LFM-A13抑制BTK，减少骨髓瘤细胞向基质细胞衍生因子-1(SDF-1)的迁移。在SCID-Rab模型中，通过生物发光成像，LFM-A13的预处理也减少了骨髓瘤细胞对骨的体内归巢。BTK在骨髓瘤细胞系中的增强表达促进了细胞向SDF-1的迁移，但对短期生长没有影响。在骨髓瘤细胞中，BTK基因和蛋白的表达与细胞表面CXCR4的表达呈正相关(n=33，r=0.81P<；0.0001)，且BTK基因和蛋白在表达CXCR4的骨髓瘤细胞中的表达更为深入。BTK不受IL-6的上调，其抑制对骨髓瘤细胞的IL-6信号转导无影响。人破骨细胞前体细胞也表达BTK和细胞表面CXCR4，并向SDF-1迁移。LFM-A13抑制破骨细胞前体细胞的迁移和分化以及成熟破骨细胞的骨吸收活性。在携带骨髓瘤的SCID-Rab小鼠中，LFM-A13抑制破骨细胞活性，防止骨髓瘤诱导的骨吸收，并适度抑制骨髓瘤的生长。这些数据表明，BTK和细胞表面CXCR4在骨髓瘤细胞中的结合，以及BTK在骨髓瘤细胞归巢到骨和骨髓瘤引起的骨病中发挥作用。
Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton’s tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL) –6– or stroma–dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM-A13, reduced their migration toward stromal cell-derived factor-1 (SDF-1). Pretreatment with LFM-A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID-rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF-1 but had no effect on short-term growth. BTK expression was correlated with cell-surface CXCR4 expression in myeloma cells (n = 33, r = 0.81, P < 0.0001), and BTK gene and protein expression was more profound in cell-surface CXCR4-expressing myeloma cells. BTK was not upregulated by IL-6 while its inhibition had no effect on IL-6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell-surface CXCR4 and migrated toward SDF-1. LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell-surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma-induced bone disease.
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影响因子：
56.9
作者：
RAWLINGS, DJ;SAFFRAN, DC;WITTE, ON
通讯作者：
WITTE, ON
影响因子：
20.3
作者：
Tai, Yu-Tzu;Chang, Betty Y.;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
4.1
作者：
Wright, LM;Maloney, W;Osdoby, P
通讯作者：
Osdoby, P
DOI：
10.1084/jem.184.1.31
发表时间：
1996-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Takata M;Kurosaki T
通讯作者：
Kurosaki T
影响因子：
20.3
作者：
Ponader, Sabine;Chen, Shih-Shih;Burger, Jan A.
通讯作者：
Burger, Jan A.