The oncogenic tyrosine kinase BCR-ABL activates a variety of signaling pathways and plays a causative role in the pathogenesis of chronic myelogenous leukemia (CML); however, the subcellular distribution of this chimeric protein remains controversial. Here, we report that BCR-ABL is localized to stress granules and that its granular localization contributes to BCR-ABL-dependent leukemogenesis. BCR-ABL-positive granules were not colocalized with any markers for membrane-bound organelles but were colocalized with HSP90a, a component of RNA granules. The number of such granules increased with thapsigargin treatment, confirming that the granules were stress granules. Given that treatment with the ABL kinase inhibitor imatinib and elimination of the N-terminal region of BCR-ABL abolished granule formation, kinase activity and the coiled-coil domain are required for granule formation. Whereas wild-type BCR-ABL rescued the growth defect in IL-3-depleted Ba/F3 cells, mutant BCR-ABL lacking the N-terminal region failed to do so. Moreover, forced tetramerization of the N-terminus-deleted mutant could not restore the growth defect, indicating that granule formation, but not tetramerization, through its N-terminus is critical for BCR-ABL-dependent oncogenicity. Our findings together provide new insights into the pathogenesis of CML by BCR-ABL and open a window for developing novel therapeutic strategies for this disease.Key words: BCR-ABL, subcellular localization, stress granule.

中文翻译：

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BCR-ABL定位于应力颗粒有助于其致癌功能。

致癌酪氨酸激酶BCR-ABL激活多种信号传导途径，并在慢性粒细胞性白血病（CML）的发病机理中发挥重要作用；然而，这种嵌合蛋白的亚细胞分布仍然存在争议。在这里，我们报告说，BCR-ABL定位于应力颗粒，并且其颗粒定位有助于BCR-ABL依赖性白血病的发生。BCR-ABL阳性颗粒未与膜结合细胞器的任何标记物共定位，而是与HSP90a（RNA颗粒的成分）共定位。毒胡萝卜素处理后，此类颗粒的数量增加，证实该颗粒为应力颗粒。鉴于使用ABL激酶抑制剂伊马替尼治疗并消除BCR-ABL的N端区域消除了颗粒形成，颗粒形成需要激酶活性和卷曲螺旋结构域。野生型BCR-ABL挽救了IL-3耗尽的Ba / F3细胞中的生长缺陷，而缺少N端区域的突变BCR-ABL未能做到。此外，N末端缺失突变体的强制四聚化不能恢复​​生长缺陷，这表明通过其N末端形成颗粒而不是四聚化对于BCR-ABL依赖性致癌性至关重要。我们的发现共同为BCR-ABL对CML的发病机理提供了新的见解，并为开发该病的新治疗策略打开了一个窗口。关键词：BCR-ABL，亚细胞定位，应激颗粒。此外，N末端缺失突变体的强制四聚化不能恢复​​生长缺陷，这表明通过其N末端形成颗粒而不是四聚化对于BCR-ABL依赖性致癌性至关重要。我们的发现共同为BCR-ABL对CML的发病机理提供了新的见解，并为开发该病的新治疗策略打开了一个窗口。关键词：BCR-ABL，亚细胞定位，应激颗粒。此外，N末端缺失突变体的强制四聚化不能恢复​​生长缺陷，这表明通过其N末端形成颗粒而不是四聚化对于BCR-ABL依赖性致癌性至关重要。我们的发现共同为BCR-ABL对CML的发病机理提供了新的见解，并为开发该病的新治疗策略打开了一个窗口。关键词：BCR-ABL，亚细胞定位，应激颗粒。