The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy
The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy
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DOI：
10.1182/blood-2010-09-305649
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发表时间：
2011-02-10
期刊：
影响因子：
20.3
通讯作者：
Kay, Neil E.
中科院分区：
文献类型：
--
作者：
Ghosh, Asish K.;Secreto, Charla;Kay, Neil E.
最近，我们检测到慢性淋巴细胞白血病（CLL）血浆中B细胞来源的微泡携带组成性磷酸化的新型受体酪氨酸激酶（RTK）Axl，表明Axl是从白血病B细胞获得的。为了检查CLL中Axl的状态，我们通过Western印迹分析测定了新鲜分离的CLL B细胞中磷酸化Axl（P-Axl）的表达。我们在CLL B细胞中检测到不同水平的P-Axl，进一步的分析表明，P-Axl的表达与CLL B细胞中的其他组成性磷酸化激酶相关，包括林恩、磷酸肌醇-3激酶、SyK/zeta相关蛋白70 kDa、磷脂酶C γ 2。我们发现这些细胞内信号分子与原代CLL B细胞中的P-Axl复合。当Axl和Src激酶被Src/Abl激酶抑制剂博舒替尼（SKI-606）或Axl的特异性抑制剂（R428）靶向时，以剂量和时间依赖性方式观察到CLL B细胞凋亡的稳健诱导。因此，我们已经在CLL B细胞中鉴定了一种新的RTK，其似乎作为多个非RTK的对接位点工作并驱动白血病细胞存活信号。这些发现突出了CLL治疗的独特目标。（血。2011; 117（6）：1928-1937）
Recently, we detected that chronic lymphocytic leukemia (CLL) B-cell-derived microvesicles in CLL plasma carry a constitutively phosphorylated novel receptor tyrosine kinase (RTK), Axl, indicating that Axl was acquired from the leukemic B cells. To examine Axl status in CLL, we determined the expression of phosphorylated-Axl (P-Axl) in freshly isolated CLL B cells by Western blot analysis. We detected differential levels of P-Axl in CLL B cells, and further analysis showed that expression of P-Axl was correlated with the other constitutively phosphorylated kinases, including Lyn, phosphoinositide-3 kinase, SyK/zeta-associated protein of 70 kDa, phospholipase C gamma 2 in CLL B cells. We found that these intracellular signaling molecules were complexed with P-Axl in primary CLL B cells. When Axl and Src kinases were targeted by a Src/Abl kinase inhibitor, bosutinib (SKI-606), or a specific-inhibitor of Axl (R428), robust induction of CLL B-cell apoptosis was observed in both a dose-and time-dependent manner. Therefore, we have identified a novel RTK in CLL B cells which appears to work as a docking site for multiple non-RTKs and drives leukemic cell survival signals. These findings highlight a unique target for CLL treatment. (Blood. 2011; 117(6): 1928-1937)