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

Nature medicine | 2009

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.

Pubmed ID: 19966776 RIS Download

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R01 CA104348-05
  • Agency: NCI NIH HHS, United States
    Id: R56 CA104348
  • Agency: NCI NIH HHS, United States
    Id: R01-CA10434
  • Agency: Intramural NIH HHS, United States
    Id: Z99 CA999999
  • Agency: NCI NIH HHS, United States
    Id: R56 CA104348-06
  • Agency: NCI NIH HHS, United States
    Id: R01 CA104348

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NIH 3T3 (tool)

RRID:CVCL_0594

Cell line NIH 3T3 is a Spontaneously immortalized cell line with a species of origin Mus musculus

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