Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function
Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function
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DOI：
10.1247/csf.19033
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发表时间：
2019-01-01
影响因子：
1.5
通讯作者：
Ohba, Yusuke
中科院分区：
文献类型：
--
作者：
Kashiwagi, Sayaka;Fujioka, Yoichiro;Ohba, Yusuke
致癌酪氨酸激酶BCR-ABL激活多种信号通路，并在慢性粒细胞白血病（CML）的发病机制中起着致病作用;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是本地化的压力颗粒，其颗粒定位有助于BCR-ABL依赖性白血病。BCR-ABL阳性颗粒不与膜结合细胞器的任何标记物共定位，但仅与RNA颗粒的组分HSP 90 a共定位。这些颗粒的数量随着毒胡萝卜素处理而增加，证实这些颗粒是应激颗粒。考虑到ABL激酶抑制剂imatinih处理和BCR-ABL N末端区域的消除了颗粒形成，激酶活性和卷曲螺旋结构域是颗粒形成所必需的。而野生型BCR-ABL拯救IL-3耗尽Ba/F3细胞的生长缺陷，缺乏N-末端区域的突变BCR-ABL未能做到这一点。此外，N-末端缺失突变体的强制四聚化不能恢复生长缺陷，表明通过其N-末端的颗粒形成而不是四聚化对于BCR-ABL依赖性致癌性至关重要。我们的研究结果为BCR-ABL导致CML的发病机制提供了新的见解，并为开发这种疾病的新治疗策略打开了一扇窗户。
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 mere 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 imatinih 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.