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 Citations (Scopus)

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 2009

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HSP90 Heat-Shock Proteins
B-Cell Lymphoma
Lymphoma, Large B-Cell, Diffuse
Scaffolds
Cells
Genes
Apoptosis
Pharmacokinetics
Cell death
purine
Toxicity
Lymphoma
Cell Death
Tissue
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cerchietti, L. C., Lopes, E. C., Yang, S. N., Hatzi, K., Bunting, K. L., Tsikitas, L. A., ... 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

A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. / Cerchietti, Leandro C.; Lopes, Eloisi C.; Yang, Shao Ning; Hatzi, Katerina; Bunting, Karen L.; Tsikitas, Lucas A.; Mallik, Alka; Robles, Ana I.; Walling, Jennifer; Varticovski, Lyuba; Shaknovich, Rita; Bhalla, Kapil N.; Chiosis, Gabriela; Melnick, Ari.

In: Nature Medicine, Vol. 15, No. 12, 12.2009, p. 1369-1376.

Research output: Contribution to journalArticle

Cerchietti, LC, Lopes, EC, Yang, SN, Hatzi, K, Bunting, KL, Tsikitas, LA, Mallik, A, Robles, AI, Walling, J, Varticovski, L, Shaknovich, R, Bhalla, KN, 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, vol. 15, no. 12, pp. 1369-1376. https://doi.org/10.1038/nm.2059
Cerchietti, Leandro C. ; Lopes, Eloisi C. ; Yang, Shao Ning ; Hatzi, Katerina ; Bunting, Karen L. ; Tsikitas, Lucas A. ; Mallik, Alka ; Robles, Ana I. ; Walling, Jennifer ; Varticovski, Lyuba ; Shaknovich, Rita ; Bhalla, Kapil N. ; Chiosis, Gabriela ; Melnick, Ari. / A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. In: Nature Medicine. 2009 ; Vol. 15, No. 12. pp. 1369-1376.
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