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

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 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2017-02-022017-02
 Publikationsstatus: Erschienen
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 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1182/blood-2016-06-721423
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Titel: Blood
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 129 (5) Artikelnummer: - Start- / Endseite: 598 - 608 Identifikator: -