Abstract
The clinical utility of histone/protein deacetylase (HDAC) inhibitors in combinatorial regimens with proteasome inhibitors for patients with relapsed and refractory multiple myeloma (MM) is often limited by excessive toxicity due to HDAC inhibitor promiscuity with multiple HDACs. Therefore, more selective inhibition minimizing off-target toxicity may increase the clinical effectiveness of HDAC inhibitors. We demonstrated that plasma cell development and survival are dependent upon HDAC11, suggesting this enzyme is a promising therapeutic target in MM. Mice lacking HDAC11 exhibited markedly decreased plasma cell numbers. Accordingly, in vitro plasma cell differentiation was arrested in B cells lacking functional HDAC11. Mechanistically, we showed that HDAC11 is involved in the deacetylation of IRF4 at lysine103. Further, targeting HDAC11 led to IRF4 hyperacetylation, resulting in impaired IRF4 nuclear localization and target promoter binding. Importantly, transient HDAC11 knockdown or treatment with elevenostat, an HDAC11-selective inhibitor, induced cell death in MM cell lines. Elevenostat produced similar anti-MM activity in vivo, improving survival among mice inoculated with 5TGM1 MM cells. Elevenostat demonstrated nanomolar ex vivo activity in 34 MM patient specimens and synergistic activity when combined with bortezomib. Collectively, our data indicated that HDAC11 regulates an essential pathway in plasma cell biology establishing its potential as an emerging theraputic vulnerability in MM.
Authors
AGM Mostofa, Allison Distler, Mark B. Meads, Eva Sahakian, John J. Powers, Alexandra Achille, David Noyes, Gabriela Wright, Bin Fang, Victoria Izumi, John Koomen, Rupal Rampakrishnan, Tuan P. Nguyen, Gabriel De Avila, Ariosto S. Silva, Praneeth Sudalagunta, Rafael Renatino Canevarolo, Maria D. Coelho Siqueira Silva, Raghunandan Reddy Alugubelli, Hongyue A. Dai, Amit Kulkarni, William S. Dalton, Oliver A. Hampton, Eric A. Welsh, Jamie K. Teer, Alexandre Tungesvik, Kenneth L. Wright, Javier Pinilla-Ibarz, Eduardo M. Sotomayor, Kenneth H. Shain, Jason Brayer
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