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Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice

Qingrong Huang, Shan He, Yuanyuan Tian, Yuting Gu, Pan Chen, Changhong Li, Jiefang Huang, Yongnian Liu, Hongshuang Yu, Min Jin, Shaoyan Hu, Qing Tong, Anqi Ma, Jian Jin, Elizabeth Hexner, Henry Fung, Ran Reshef, Yi Zhang and Yanyun Zhang

Key points

  • Ezh2 requires Hsp90 to maintain the Ezh2 protein stability and function in alloreactive T cells.

  • Pharmacological inhibition of Hsp90 destabilizes Ezh2 protein in alloreactive T cells, reduces GVHD but preserves GVL effects.

Abstract

Modulating T cell alloreactivity has been a main strategy to reduce graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Genetic deletion of T cell Ezh2, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3), inhibits GVHD. Therefore, reducing Ezh2-mediated H3K27me3 is thought to be essential for inhibiting GVHD. We tested this hypothesis in mouse GVHD models. Unexpectedly, administration of the Ezh2 inhibitor GSK126, which specifically decreases H3K27me3 without affecting Ezh2 protein, failed to prevent the disease. In contrast, destabilizing T cell Ezh2 protein by inhibiting Hsp90 using its specific inhibitor AUY922 reduced GVHD in mice undergoing allogeneic HSCT. In vivo administration of AUY922 selectively induced apoptosis of activated T cells and decreased the production of effector cells producing IFN-γ and TNF-α, similar to genetic deletion of Ezh2. Introduction of Ezh2 into alloreactive T cells restored their expansion and production of effector cytokines upon AUY922 treatment, suggesting that impaired T cell alloreactivity by inhibiting Hsp90 is achieved mainly through depleting Ezh2. Mechanistic analysis revealed that the enzymatic SET domain of Ezh2 directly interacted with Hsp90 to prevent Ezh2 from rapid degradation in activated T cells. Importantly, pharmacological inhibition of Hsp90 preserved anti-leukemia activity of donor T cells, leading to improved overall survival of recipient mice after allogeneic HSCT. Our findings identify the Ezh2-Hsp90 interaction as a previously unrecognized mechanism essential for T cell responses and an effective target for controlling GVHD.

  • Submitted August 29, 2016.
  • Accepted February 17, 2017.