Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation

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 combined treatment with Ganetespib plus the FGFR inhibitor BGJ398. Collectively, these data suggest novel therapeutic approaches for future stem cell leukemia/lymphoma treatment: inhibition of BCR oligomerization by disruption of required salt bridges; and inhibition of the chaperonin Hsp90 complex.

Protein kinase C fusion proteins are paradoxically loss of function in cancer

“…These well-characterized fusions result in kinases with truncated regulatory domains, resulting in constitutive activity. In addition to BCR-ABL, fusions of the kinase domain of PKA in DNAJB1-PRKACA and the kinase domain of various FGFR isozymes (e.g., FGFR3-TACC3, BCR-FGFR1) drive tumorigenesis because of their unregulated activity (68)(69)(70)(71)(72). Our analysis of 3' PKC fusions reveals that these fusions are also constitutively active due to loss of regulatory constraints.…”

Oncogenic fusion protein FGFR2-PPHLN1: Requirements for biological activation, and efficacy of inhibitors

“…This observed phenotype could be attributed to access to essential downstream adaptor proteins such as FRS-2 that mediate FGFR signaling pathways. Not all oncogenic fusion proteins involving RTKs necessarily require membrane association, however, as evidenced by the apparently cytoplasmic/nuclear localization of BCR-ABL and BCR-FGFR1 [ 33 , 34 ]. Due to the localization requirement of FGFR2-PPHLN1, inhibition of membrane localization could serve as an alternative therapeutic strategy in targeting FGFR2-PPHLN1-driven ICC.…”

Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

“…FGFR1 rearrangements are not cryptic; hence, they can be diagnosed by conventional cytogenetic analyses [ 73 ]. The most common fusions are represented by Zinc finger MYM-type protein 2 ( ZMYM2)-FGFR1 ( ZMYM2 exon 17– FGFR1 exon 9: 40%), BCR-FGFR1 ( BCR exon 4– FGFR1 exon 9: 18%), and Centriolin-FGFR1 [ CNTRL (CEP110) exon 15– FGFR1 exon 9: 15%) [ 30 , 35 , 74 , 75 ] ( Figure 3 ). In all of these pathologic fusions, the improper constitutive activation of the FGFR1 catalytic domain drives disease initiation and progression.…”