TitleA purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas.
Publication TypeJournal Article
Year of Publication2009
AuthorsCerchietti, 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, and Melnick Ari
JournalNat Med
Volume15
Issue12
Pagination1369-76
Date Published2009 Dec
ISSN1546-170X
KeywordsDNA-Binding Proteins, HSP90 Heat-Shock Proteins, Humans, Lymphoma, B-Cell, Protein Binding, Proto-Oncogene Proteins c-bcl-6
Abstract

<p>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.</p>

DOI10.1038/nm.2059
Alternate JournalNat Med
PubMed ID19966776
PubMed Central IDPMC2805915
Grant ListR01 CA104348-05 / CA / NCI NIH HHS / United States
R56 CA104348 / CA / NCI NIH HHS / United States
R01-CA10434 / CA / NCI NIH HHS / United States
Z99 CA999999 / ImNIH / Intramural NIH HHS / United States
R56 CA104348-06 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States