Tyrosinekinase inhibition facilitates cooperation of transcription factor SALL4 and ABC transporter A3 towards intrinsic CML cell drug resistance
Tyrosinekinase inhibition facilitates cooperation of transcription factor SALL4 and ABC transporter A3 towards intrinsic CML cell drug resistance
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DOI：
10.1111/bjh.12246
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发表时间：
2013-04-01
影响因子：
6.5
通讯作者：
Wulf, Gerald G.
中科院分区：
文献类型：
--
作者：
Hupfeld, Timo;Chapuy, Bjoern;Wulf, Gerald G.
尽管 BCR-ABL1 酪氨酸激酶抑制剂能够可靠地诱导慢性粒细胞白血病 (CML) 患者的疾病缓解，但为了防止持续性白血病细胞复发，必须无限延长治疗。在这里，我们分析了模型细胞系和原代 CML 细胞的 ABC 转运蛋白 A3 (ABCA3) 以及胚胎干细胞相关转录因子 SALL4 的表达和功能。 ABCA3 保护白血病细胞免受酪氨酸激酶抑制剂伊马替尼、达沙替尼和尼洛替尼的细胞毒性作用。在存活的细胞中，暴露于酪氨酸激酶抑制剂可显着增强体内和体外的 ABCA3 表达，并且与结合 ABCA3 启动子的 SALL4 表达增加相关。通过基因沉默或吲哚美辛（而非γ干扰素）对ABCA3或SALL4的抑制，中断了ABCA3的SALL4依赖性调节，并恢复了白血病细胞对酪氨酸激酶抑制的敏感性。酪氨酸激酶抑制剂暴露促进持续性白血病细胞中 SALL4 和 ABCA3 合作的保护环。
Although BCR-ABL1 tyrosine kinase inhibitors reliably induce disease remission for patients with chronic myeloid leukaemia (CML), unlimited extension of therapy is necessary to prevent relapse from persistent leukaemic cells. Here, we analysed model cell lines and primary CML cells for the expression and functions of the ABC transporter A3 (ABCA3) as well as the embryonic stem cell-associated transcription factor SALL4. ABCA3 protected leukaemic cells from the cytotoxic effects of the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. In the surviving cells, exposure to tyrosine kinase inhibitors significantly enhanced ABCA3 expression in vivo and in vitro, and was associated with increased expression of SALL4, which binds the ABCA3 promoter. Inhibition of ABCA3 or SALL4 by genetic silencing or indomethacin, but not interferon gamma, interrupted SALL4-dependent regulation of ABCA3 and restored susceptibility of leukaemic cells to tyrosine kinase inhibition. Tyrosine kinase inhibitor exposure facilitates a protective loop of SALL4 and ABCA3 cooperation in persistent leukaemic cells.