Cargando…

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

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. T...

Descripción completa

Detalles Bibliográficos
Autores principales: Peiris, Malalage N., Meyer, April N., Nelson, Katelyn N., Bisom-Rapp, Ezra W., Donoghue, Daniel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193502/
https://www.ncbi.nlm.nih.gov/pubmed/31439673
http://dx.doi.org/10.3324/haematol.2019.220871
_version_ 1783528208694509568
author Peiris, Malalage N.
Meyer, April N.
Nelson, Katelyn N.
Bisom-Rapp, Ezra W.
Donoghue, Daniel J.
author_facet Peiris, Malalage N.
Meyer, April N.
Nelson, Katelyn N.
Bisom-Rapp, Ezra W.
Donoghue, Daniel J.
author_sort Peiris, Malalage N.
collection PubMed
description 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/lymphoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-cell lymphoma. This work focuses on the 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, 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 disruption 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 treatment: inhibition of BCR oligomerization by disruption of required salt bridges; and inhibition of the chaperonin Hsp90 complex.
format Online
Article
Text
id pubmed-7193502
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Ferrata Storti Foundation
record_format MEDLINE/PubMed
spelling pubmed-71935022020-05-11 Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation Peiris, Malalage N. Meyer, April N. Nelson, Katelyn N. Bisom-Rapp, Ezra W. Donoghue, Daniel J. Haematologica Articles 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/lymphoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-cell lymphoma. This work focuses on the 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, 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 disruption 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 treatment: inhibition of BCR oligomerization by disruption of required salt bridges; and inhibition of the chaperonin Hsp90 complex. Ferrata Storti Foundation 2020-05 /pmc/articles/PMC7193502/ /pubmed/31439673 http://dx.doi.org/10.3324/haematol.2019.220871 Text en Copyright© 2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Articles
Peiris, Malalage N.
Meyer, April N.
Nelson, Katelyn N.
Bisom-Rapp, Ezra W.
Donoghue, Daniel J.
Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation
title Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation
title_full Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation
title_fullStr Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation
title_full_unstemmed Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation
title_short Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation
title_sort oncogenic fusion protein bcr-fgfr1 requires the breakpoint cluster region-mediated oligomerization and chaperonin hsp90 for activation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193502/
https://www.ncbi.nlm.nih.gov/pubmed/31439673
http://dx.doi.org/10.3324/haematol.2019.220871
work_keys_str_mv AT peirismalalagen oncogenicfusionproteinbcrfgfr1requiresthebreakpointclusterregionmediatedoligomerizationandchaperoninhsp90foractivation
AT meyerapriln oncogenicfusionproteinbcrfgfr1requiresthebreakpointclusterregionmediatedoligomerizationandchaperoninhsp90foractivation
AT nelsonkatelynn oncogenicfusionproteinbcrfgfr1requiresthebreakpointclusterregionmediatedoligomerizationandchaperoninhsp90foractivation
AT bisomrappezraw oncogenicfusionproteinbcrfgfr1requiresthebreakpointclusterregionmediatedoligomerizationandchaperoninhsp90foractivation
AT donoghuedanielj oncogenicfusionproteinbcrfgfr1requiresthebreakpointclusterregionmediatedoligomerizationandchaperoninhsp90foractivation