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  HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B cell receptor signaling.

Walter, R., Pan, K. T., Doebele, C., Comoglio, F., Tomska, K., Bohnenberger, H., et al. (2017). HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B cell receptor signaling. Blood, 129(5), 598-608. doi:10.1182/blood-2016-06-721423.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-5A54-8 Version Permalink: http://hdl.handle.net/21.11116/0000-0001-55A8-2
Genre: Journal Article

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 Creators:
Walter, R., Author
Pan, K. T.1, Author              
Doebele, C., Author
Comoglio, F., Author
Tomska, K., Author
Bohnenberger, H., Author
Young, R. M., Author
Jacobs, L., Author
Keller, U., Author
Bönig, H., Author
Engelke, M., Author
Rosenwald, A., Author
Urlaub, H.1, Author              
Staudt, L. M., Author
Serve, H., Author
Zenz, T., Author
Oellerich, T., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              

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 Abstract: Burkitt lymphoma (BL) is an aggressive B cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Due to their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells. By global proteomic and phosphoproteomic profiling we show that in BL, HSP90 inhibition compromises the activity of the pivotal B cell antigen receptor (BCR)-proximal effector spleen tyrosine kinase (SYK), which we identified as an HSP90 client protein. Consistently, expression of constitutively active TEL-SYK counteracted the apoptotic effect of HSP90 inhibition. Together, our results demonstrate that HSP90 inhibition impairs BL cell survival by interfering with tonic BCR signaling, thus providing a molecular rationale for the use of HSP90 inhibitors in the treatment of BL.

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Language(s): eng - English
 Dates: 2017-02-022017-02
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1182/blood-2016-06-721423
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Title: Blood
Source Genre: Journal
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Pages: - Volume / Issue: 129 (5) Sequence Number: - Start / End Page: 598 - 608 Identifier: -