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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.

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Figure 1: Hsp90 inhibition induces apoptosis preferentially in BCL-6–dependent DLBCL.
Figure 2: BCL-6 is an Hsp90 target protein.
Figure 3: Hsp90 prevents BCL-6 mRNA decay.
Figure 4: Hsp90 is expressed in the nuclear and cytoplasmic compartments of DLBCLs, and primary cells respond to PU-H71.
Figure 5: PU-H71 suppresses DLBCL xenografts.
Figure 6: PU-H71 induces additional changes in protein abundance and a specific gene expression signature in DLBCLs.

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Acknowledgements

We thank J.C. Zenklusen for his contribution with gene expression profiling, D. Zatorska for the synthesis of PU-H71, L. Neckers (Urologic Oncology Branch, National Cancer Institute) for providing pGEM4Z Hsp90 vectors, V. Bardwell (University of Minnesota) for providing T7plink vectors, M. Shipp (Dana-Farber Cancer Center) for providing cell lines, and B.H. Ye (Albert Einstein College of Medicine) for providing FUW-hBCL-6 plasmid constructs and cell lines. G.C. is supported by the Geoffrey Beene Cancer Research Center of the Memorial Sloan-Kettering Cancer Center, Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Leukemia and Lymphoma Society, the Translational and Integrative Medicine Research Fund and the Experimental Therapeutics Center of the Memorial Sloan-Kettering Cancer Center. A. Melnick is supported by the Leukemia and Lymphoma Society grant S-7032-04, US National Cancer Institute grant R01-CA10434 and the Chemotherapy Foundation. This research was supported in part by the Intramural Research Program of the US National Institutes of Health National Cancer Institute Center for Cancer Research.

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L.C.C., G.C. and A. Melnick conceived of the project. L.C.C., E.C.L., S.N.Y., K.H., K.L.B., L.A.T., A. Mallik, A.I.R., J.W. and R.S. performed experiments and analyzed data. L.C.C., E.C.L., A. Melnick, L.V., K.N.B. and G.C. designed the studies and supervised research. K.N.B. and L.V. gave scientific advice. L.C.C., A. Melnick and G.C. wrote the manuscript.

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Correspondence to Gabriela Chiosis or Ari Melnick.

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Cerchietti, L., Lopes, E., Yang, S. et al. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6–dependent B cell lymphomas. Nat Med 15, 1369–1376 (2009). https://doi.org/10.1038/nm.2059

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