A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas

Leandro C. Cerchietti, Eloisi C. Lopes, Shao Ning Yang, Katerina Hatzi, Karen L. Bunting, Lucas A. Tsikitas, Alka Mallik, Ana I. Robles, Jennifer Walling, Lyuba Varticovski, Rita Shaknovich, Kapil N. Bhalla, Gabriela Chiosis, Ari Melnick

Research output: Contribution to journalArticle

120 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1369-1376
Number of pages8
JournalNature medicine
Volume15
Issue number12
DOIs
StatePublished - Dec 1 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas'. Together they form a unique fingerprint.

  • Cite this

    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. (2009). A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nature medicine, 15(12), 1369-1376. https://doi.org/10.1038/nm.2059