A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas Journal Article
| Authors: | Cerchietti, L. C.; Lopes, E. C.; Yang, S. N.; Hatzi, K.; Bunting, K. L.; Tsikitas, L. A.; Mallik, A.; Robles, A. I.; Walling, J.; Varticovski, L.; Shaknovich, R.; Bhalla, K. N.; Chiosis, G.; Melnick, A. |
| Article Title: | A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas |
| Abstract: | We report that heat shock protein 90 (Hsp90) inhibitors selectively kill diffuse large B cell lymphomas (DLBCLs) that depend on the BCL-6 transcriptional repressor. We found that endogenous Hsp90 interacts with BCL-6 in DLBCL cells and can stabilize BCL-6 mRNA and protein. Hsp90 formed a complex with BCL-6 at its target promoters, and Hsp90 inhibitors derepressed BCL-6 target genes. A stable mutant of BCL-6 rescued DLBCL cells from Hsp90 inhibitor-induced apoptosis. BCL-6 and Hsp90 were almost invariantly coexpressed in the nuclei of primary DLBCL cells, suggesting that their interaction is relevant in this disease. We examined the pharmacokinetics, toxicity and efficacy of PU-H71, a recently developed purine-derived Hsp90 inhibitor. PU-H71 preferentially accumulated in lymphomas compared to normal tissues and selectively suppressed BCL-6-dependent DLBCLs in vivo, inducing reactivation of key BCL-6 target genes and apoptosis. PU-H71 also induced cell death in primary human DLBCL specimens. © 2009 Nature America, Inc. All rights reserved. |
| Keywords: | protein kinase b; controlled study; protein expression; treatment response; unclassified drug; human cell; promoter region; dna-binding proteins; raf protein; drug efficacy; nonhuman; mutant protein; mouse; actin; animal tissue; complex formation; apoptosis; protein protein interaction; animal experiment; animal model; protein binding; protein stability; in vivo study; antineoplastic activity; drug potency; drug selectivity; b cell lymphoma; lymphoma, b-cell; messenger rna; nucleotide sequence; histone h3; heat shock protein 90 inhibitor; pu h71; heat shock protein 90; hsp90 heat-shock proteins; beta 2 microglobulin; glyceraldehyde 3 phosphate dehydrogenase; heat shock protein 27; heat shock protein 70; i kappa b kinase gamma; protein bcl 6; cell nucleus; rna stability |
| Journal Title: | Nature Medicine |
| Volume: | 15 |
| Issue: | 12 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2009-12-01 |
| Start Page: | 1369 |
| End Page: | 1376 |
| Language: | English |
| DOI: | 10.1038/nm.2059 |
| PUBMED: | 19966776 |
| PROVIDER: | scopus |
| PMCID: | PMC2805915 |
| DOI/URL: | |
| Notes: | --- Erratum issued, see DOI: 10.1038/s41591-024-02957-0 -- "Cited By (since 1996): 8" -- "Export Date: 30 November 2010" -- "CODEN: NAMEF" -- "Source: Scopus" |
