Two major types of leukemogenic BCR-ABL fusion proteins are p190BCR-ABLand p210BCR-ABL. Although the two fusion proteins are closely related, they can lead to different clinical outcomes. A thorough understanding of the signaling programs employed by these two fusion proteins is necessary to explain these clinical differences. We took an integrated approach by coupling protein–protein interaction analysis using biotinylation identification with global phosphorylation analysis to investigate the differences in signaling between these two fusion proteins. Our findings suggest that p190BCR-ABL and p210BCR-ABL differentially activate important signaling pathways, such as JAK-STAT, and engage with molecules that indicate interaction with different subcellular compartments. In the case of p210BCR-ABL, we observed an increased engagement of molecules active proximal to the membrane and in the case of p190BCR-ABL, an engagement of molecules of the cytoskeleton. These differences in signaling could underlie the distinct leukemogenic process induced by these two protein variants.
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This study was supported by NCI’s Clinical Proteomic Tumor Analysis Consortium Initiative (U24CA160036) and a shared instrumentation grant (S10OD021844). JC was supported by NIGMS Training Grant 5T32GM07814. We thank Saradhi Mallampati for his support, the Center for Proteomics Discovery at Johns Hopkins, Rieke Jenson for graphic design consultation and all the members of the Reddy and Pandey laboratories.
JAC completed all experiments and carried out data analysis. JAC, KR and AP wrote the manuscript. JAC, T-CH, KR and AP conceived the experimental idea. JAC, KR and AP designed and planned all experiments. RT and SS helped optimize experimental conditions. RT, SKS, XWu, AHP and CM assisted with data analysis. RT and XWu helped optimize validation effort. MH helped establish and optimize the BCR-ABL MPP system. XWo, KR, M-SK and RSN helped optimize BioID protocols. SR carried out mass spectrometry analysis.
The authors declare no conflict of interest.
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Cutler, J., Tahir, R., Sreenivasamurthy, S. et al. Differential signaling through p190 and p210 BCR-ABL fusion proteins revealed by interactome and phosphoproteome analysis. Leukemia 31, 1513–1524 (2017). https://doi.org/10.1038/leu.2017.61
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