Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function

Abstract

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.

Stress Granules Involved in Formation, Progression and Metastasis of Cancer: A Scoping Review

“…The percentage of various studies is shown in Figure 2. Meanwhile, the majority of studies, about 66% of studies, are dedicated to cell culture studies only (Baguet et al, 2007;Miyoshi et al, 2007;Arimoto et al, 2008;Eisinger-Mathason et al, 2008;Goulet et al, 2008;Busà et al, 2010;Gottschald et al, 2010;Guo et al, 2010;Kalra et al, 2010;Nikpour et al, 2011;Taniuchi et al, 2011aTaniuchi et al, ,b, 2014Park et al, 2012;Fournier et al, 2013;Pizzo et al, 2013;Thedieck et al, 2013;Chang et al, 2014;Kano et al, 2014;Podszywalow-Bartnicka et al, 2014;Yuan et al, 2014;Liu et al, 2015;Somasekharan et al, 2015;Szafron et al, 2015;Valentin-Vega et al, 2016;Weeks et al, 2016;Narayanan et al, 2017;Wall and Lewis, 2017;Takayama et al, 2018;Haghandish et al, 2019;Heberle et al, 2019;Kashiwagi et al, 2019;Mazloomian et al, 2019;Cui et al, 2020;Do et al, 2020;Brown et al, 2021).…”

“…HuR influenced BRCA1 translation and mRNA stability positively (Podszywalow-Bartnicka et al, 2014). It should be noted that the oncogenic tyrosine kinase BCR-ABL is also localized in the structure of SGs, and the formation of granular structure is necessary for the activity of ABL kinase and N-terminal region of BCR (Kashiwagi et al, 2019).…”

Fusion genes as diagnostic and predictive biomarkers for tumor

“…ABL is another famous tyrosine kinase that has DNA-binding activity and is involved in apoptosis and DNA damage repair; CML could be resulted due to the juxtaposition of ABL to BCR protein [48] . The fusion proteins are characterized as having liquid-like properties, while the ABL kinase activity is necessary for promoting oncogenesis [49] . The fusion proteins activate pathways involved in cell proliferation, adhesion, differentiation, and cell survival [48] , and promote the enrichment of stress granules [49] .…”

“…The fusion proteins are characterized as having liquid-like properties, while the ABL kinase activity is necessary for promoting oncogenesis [49] . The fusion proteins activate pathways involved in cell proliferation, adhesion, differentiation, and cell survival [48] , and promote the enrichment of stress granules [49] . It is believed that the fusion protein alters the properties and composition of stress granules.…”

A method for the generation of pseudotyped virus particles bearing SARS coronavirus spike protein in high yields

“…Fluorescence imaging and data analysis were performed essentially as described previously (Fujioka et al, 2019;Kashiwagi et al, 2019b). In brief, cells transfected with mCherry-CoV-S or mCherry-CoV-2-S vectors were stained with Hoechst 33342 for 15 min and placed in a stage-top incubation chamber maintained at 37°C on a Nikon Ti2 microscope (Nikon, Tokyo, Japan) equipped with a Zyla5.5 scientific complementary metal oxide semiconductor camera (Oxford Instruments, Belfast, UK).…”