Oncogenic fusion protein BCR-FGFR1 requires BCR-mediated oligomerization and chaperonin Hsp90 for activation.
Oncogenic fusion protein BCR-FGFR1 requires BCR-mediated oligomerization and chaperonin Hsp90 for activation.
Haematologica. 2019 Aug 22;:
Authors: Peiris MN, Meyer AN, Nelson KN, Bisom-Rapp EW, Donoghue DJ
Abstract
Mutation and translocation of fibroblast growth factor receptors often lead to aberrant signaling and cancer. This work focuses on the t(8;22)(p11;q11) chromosomal translocation which creates the BCR-FGFR1 fusion protein. This fusion occurs in stem cell leukemia/lymphoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-Cell lymphoma. This work focuses on biochemical characterization of BCR-FGFR1 and identification of novel therapeutic targets. The tyrosine kinase activity of FGFR1 is required for biological activity as shown using transformation assays, IL-3 independent cell proliferation, and liquid chromatography/mass spectroscopy analyses. Furthermore, BCR contributes a coiled-coil oligomerization domain, also essential for oncogenic transformation by BCR-FGFR1. The importance of salt bridge formation within the coiled-coil domain is demonstrated, as disruption of three salt bridges abrogates cellular transforming ability. Lastly, BCR-FGFR1 acts as a client of the chaperone protein Hsp90, suggesting that BCR-FGFR1 relies on the Hsp90 complex to evade proteasomal degradation. Transformed cells expressing BCR-FGFR1 are sensitive to the Hsp90 inhibitor Ganetespib, and also respond to ...
Source: Haematologica - Category: Hematology Authors: Peiris MN, Meyer AN, Nelson KN, Bisom-Rapp EW, Donoghue DJ Tags: Haematologica Source Type: research
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