Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function.
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.
['Kashiwagi|Sayaka|S|', 'Fujioka|Yoichiro|Y|', 'Kondo|Takeshi|T|', 'Satoh|Aya O|AO|', 'Yoshida|Aiko|A|', 'Fujioka|Mari|M|', 'Sasajima|Hitoshi|H|', 'Amano|Maho|M|', 'Teshima|Takanori|T|', 'Ohba|Yusuke|Y|']
D063646:Carcinogenesis D049109:Cell Proliferation D002470:Cell Survival D003594:Cytoplasmic Granules D016044:Fusion Proteins, bcr-abl D006801:Humans D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive D061848:Optical Imaging D013312:Stress, Physiological D014407:Tumor Cells, Cultured
BCR-ABL stress granule subcellular localization