Targeting of the N-terminal coiled coil oligomerization interface of BCR interferes with the transformation potential of BCR-ABL and increases sensitivity to STI571
Targeting of the N-terminal coiled coil oligomerization interface of BCR interferes with the transformation potential of BCR-ABL and increases sensitivity to STI571
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DOI：
10.1182/blood-2003-03-0811
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发表时间：
2003-10-15
期刊：
影响因子：
20.3
通讯作者：
Ruthardt, M
中科院分区：
文献类型：
--
作者：
Beissert, T;Puccetti, E;Ruthardt, M
涉及9号染色体上abl基因座的易位将酪氨酸激酶c-ABL融合到具有寡聚化界面的蛋白质如BCR或TEL，使得这些ABL融合蛋白（X-ABL）能够转化细胞并诱导白血病。ABL激酶活性被ABL激酶抑制剂STI 571阻断，从而消除X-ABL的转化。为了研究寡聚化对X-ABL转化潜力和对STI 571的敏感性的作用，我们构建了具有参与白血病相关易位的蛋白质如BCR、TEL、PML和PLZF的寡聚化界面的ABL嵌合体。我们评估了这些嵌合体与p185（（BCR-ABL））相比形成高分子量（HMW）复合物的能力。这些嵌合体形成的HMW复合物的大小与它们在Ba/F3细胞中诱导因子独立性的能力之间存在直接关系，而HMW复合物的大小与对STI 571的敏感性之间存在反比关系。通过代表BCR卷曲螺旋区域的肽靶向P185（（BCR-ABL））的寡聚化界面降低了其转化成纤维细胞的潜力并增加了对STI 571的敏感性。我们的结果表明，靶向X-ABL的寡聚化界面增强了STI 571在治疗由X-ABL引起的白血病中的作用。2003;102：2985-2993）（C）2003年由美国血液学会。
Translocations involving the abl locus on chromosome 9 fuses the tyrosine kinase c-ABL to proteins harboring oligomerization interfaces such as BCR or TEL, enabling these ABL-fusion proteins (X-ABL) to transform cells and to induce leukemia. The ABL kinase activity is blocked by the ABL kinase inhibitor STI571 which abrogates transformation by X-ABL. To investigate the role of oligomerization for the transformation potential of X-ABL and for the sensitivity to STI571, we constructed ABL chimeras with oligomerization interfaces of proteins involved in leukemia-associated translocations such as BCR, TEL, PML, and PLZF. We assessed the capacity of these chimeras to form high molecular weight (HMW) complexes as compared with p185((BCR-ABL)). There was a direct relationship between the size of HMW complexes formed by these chimeras and their capacity to induce factor independence in Ba/F3 cells, whereas there was an inverse relationship between the size of the HMW complexes and the sensitivity to STI571. The targeting of the oligomerization interface of P185((BCR-ABL)) by a peptide representing the coiled coil region of BCR reduced its potential to transform fibroblasts and increased sensitivity to STI571. Our results indicate that targeting of the oligomerization interfaces of the X-ABL enhances the effects of STI571 in the treatment of leukemia caused by X-ABL. (Blood. 2003;102: 2985-2993) (C) 2003 by The American Society of Hematology.