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Fusion tyrosine kinases: a result and cause of genomic instability

Abstract

Reciprocal chromosomal translocations may arise as a result of unfaithful repair of spontaneous DNA double-strand breaks, most probably induced by oxidative stress, radiation, genotoxic chemicals and/or replication stress. Genes encoding tyrosine kinases are targeted by these mechanisms resulting in the generation of chimera genes encoding fusion tyrosine kinases (FTKs). FTKs display transforming activity owing to their constitutive kinase activity causing deregulated proliferation, apoptosis, differentiation and adhesion. Moreover, FTKs are able to facilitate DNA repair, prolong activation of G2/M and S cell cycle checkpoints, and elevate expression of antiapoptotic protein Bcl-XL, making malignant cells less responsive to antitumor treatment. FTKs may also stimulate the generation of reactive oxygen species and enhance spontaneous DNA damage in tumor cells. Unfortunately, FTKs compromise the fidelity of DNA repair mechanisms, which contribute to the accumulation of additional genetic abnormalities leading to the resistance to inhibitors such as imatinib mesylate and malignant progression of the disease.

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Acknowledgements

TS was supported by the grants from NIH/NCI, American Cancer Society, and Department of Defense. ETPP was sponsored by the Physician Scientist Training Program 5R25DK059644-05 from NIH/NIDDK.

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Penserga, E., Skorski, T. Fusion tyrosine kinases: a result and cause of genomic instability. Oncogene 26, 11–20 (2007). https://doi.org/10.1038/sj.onc.1209756

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