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Haematologica 2020 Volume 105(5):1262-1273
Myeloproliferative Neoplasm
Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation
Malalage N. Peiris,1 April N. Meyer,1 Katelyn N. Nelson,1 Ezra W. Bisom-Rapp,1 and Daniel J. Donoghue1,2
1Department of Chemistry and Biochemistry, University of California San Diego and 2Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
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 breakpoint cluster region (BCR) fibroblast growth factor receptor1 (FGFR1) (BCR-FGFR1) fusion protein. This fusion occurs in stem cell leukemia/lym- phoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-cell lymphoma. This work focuses on the biochem- ical characterization of BCR-FGFR1 and identification of novel therapeutic targets. The tyrosine kinase activity of FGFR1 is required for biological activ- ity as shown using transformation assays, interleukin-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 dis- ruption of three salt bridges abrogates cellular transforming ability. Lastly, BCR-FGFR1 acts as a client of the chaperonin heat shock protein 90 (Hsp90), suggesting that BCR-FGFR1 relies on 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 treat- ment: inhibition of BCR oligomerization by disruption of required salt bridges; and inhibition of the chaperonin Hsp90 complex.
Introduction
Fibroblast growth factor receptors (FGFR) are part of the receptor tyrosine kinase (RTK) family and are responsible for cell growth and proliferation. The FGFR fam- ily is composed of four homologous receptors; all contain three extracellular immunoglobulin-like domains, a transmembrane domain, and a split kinase domain. When these receptors are bound to fibroblast growth factor (FGF) and heparin sulfate proteoglycans, they are able to dimerize, which leads to auto-phos- phorylation of the kinase domain and activation of downstream cell signaling path- ways including signal transducer and activator of transcription (STAT), mitogen activated protein kinase (MAPK), protein kinase B (AKT), and phospholipase C gamma (PLCγ). FGFR signaling results in cellular migration, cell proliferation, angio- genesis, and wound healing.1
FGFRs are often aberrantly activated in cancer by overexpression, mutation, or translocation. Specifically, FGFR1 is involved in stem cell leukemia/lymphoma (SCLL), also known as 8p11 myeloproliferative syndrome (EMS).2 SCLL is charac- terized by a chromosomal translocation that produces a dimerizing protein partner fused to the kinase domain of FGFR1.3 Although SCLL is rare, it can aggressively progress to atypical chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or B-cell lymphoma. Despite extensive chemotherapy, the only known cur-
Correspondence:
DANIEL J. DONOGHUE
ddonoghue@ucsd.edu
Received: March 1, 2019. Accepted: August 14, 2019. Pre-published: August 22, 2019.
doi:10.3324/haematol.2019.220871
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1262
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