BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition
BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition
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DOI：
10.1038/nature09883
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发表时间：
2011-05-19
期刊：
影响因子：
64.8
通讯作者：
Mueschen, Markus
中科院分区：
文献类型：
--
作者：
Duy, Cihangir;Hurtz, Christian;Mueschen, Markus
酪氨酸激酶抑制剂(TKIs)被广泛用于治疗由bcr-abl1(参考文献1)驱动的白血病患者。1)和其他致癌酪氨酸激酶(2，3)。最近的努力集中在开发更有效的TKI，也抑制突变的酪氨酸激酶(4，5)。然而，即使有效的TKI通常也无法根除白血病起始细胞(LIC)(6-8)，这些细胞通常在最初成功治疗后导致白血病复发。在这里，我们报告了一种新的耐药机制的发现，该机制基于白血病细胞对TKI治疗的保护性反馈信号。我们认为BCL6是这种耐药途径的中心成分，并证明靶向抑制BCL6可以根除耐药和引发白血病的亚克隆。
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases(2,3). Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases(4,5). However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs)(6-8), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.