Targeting of the N-terminal coiled coil oligomerization interface by a Helix-2 peptide inhibits unmutated and imatinib-resistant BCR/ABL
Targeting of the N-terminal coiled coil oligomerization interface by a Helix-2 peptide inhibits unmutated and imatinib-resistant BCR/ABL
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DOI：
10.1002/ijc.23467
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发表时间：
2008-06-15
影响因子：
6.4
通讯作者：
Ruthardt, Martin
中科院分区：
文献类型：
--
作者：
Beissert, Tim;Hundertmark, Alena;Ruthardt, Martin
BCR/ABL 癌基因导致费城染色体阳性 (Ph+) 白血病的表型。 BCR/ABL 表现出异常的 ABL-酪氨酸激酶活性。使用选择性 ABL 激酶抑制剂（如伊马替尼、尼罗替尼和达沙替尼）治疗晚期 Ph+ 白血病最初有效，但很快就会出现耐药性，主要是因为 BCR/ABL 的特定突变。 ABL 通过 BCR N 末端卷曲螺旋区域 (CC) 的四聚化对于 ABL 激酶激活至关重要。靶向 CC 结构域迫使 BCR/ABL 形成单体构象，降低其激酶活性并增加对伊马替尼的敏感性。我们表明，(i) 通过代表 CC 的 Helix-2 的肽来靶向四聚化，可有效降低未突变和突变的 BCR/ABL 的自身磷酸化； (ii) Helix-2 抑制 BCR/ABL 的转化潜力，与突变的存在无关； (iii) Helix-2 与伊马替尼有效配合，这通过它们对转化潜力和与 BCR/ABL 相关的因子独立性的影响（突变体 T315I 除外）来揭示。这些发现支持了早期的观察结果，即携带 T315I 突变的 BCR/ABL 具有至少部分独立于其激酶活性的转化潜力。这些数据提供的证据表明，四聚化的抑制会抑制 BCR/ABL 介导的转化，并有助于克服伊马替尼耐药性。 (C) 2008 Wiley-Liss, Inc.
The BCR/ABL oncogene is responsible for the phenotype of Philadelphia chromosome-positive (Ph+) leukemia. BCR/ABL exhibits an aberrant ABL-tyrosine kinase activity. The treatment of advanced Ph+ leukemia with selective ABL-kinase inhibitors such as Imatinib, Nilotinib and Dasatinib is initially effective but rapidly followed by resistance mainly because of specific mutations in BCR/ABL. Tetramerization of ABL through the N-terminal coiled-coil region (CC) of BCR is essential for the ABL-kinase activation. Targeting the CC-domain forces BCR/ABL into a monomeric conformation reduces its kinase activity and increases the sensitivity for Imatinib. We show that (i) targeting the tetramerization by a peptide representing the Helix-2 of the CC efficiently reduced the autophosphorylation of both unmutated and mutated BCR/ABL; (ii) Helix-2 inhibited the transformation potential of BCR/ABL independently of the presence of mutations; and (iii) Helix-2 efficiently cooperated with Imatinib as revealed by their effects on the transformation potential and the factor-independence related to BCR/ABL with the exception of mutant T315I. These findings support earlier observations that BCR/ABL harboring the T315I mutation have a transformation potential that is at least partially independent of its kinase activity. These data provide evidence that the inhibition of tetramerization inhibits BCR/ABL-mediated transformation and can contribute to overcome Imatinib-resistance. (C) 2008 Wiley-Liss, Inc.