Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes suggérant l'intérêt d'un inhibiteur des histones désacétylases HDAC1 et HDAC2 pour le traitement des patients atteints d'une leucémie lymphoblastique aiguë B
Purpose: Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small molecule inhibitors that target epigenetic mechanisms. Experimental Design: A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B cell malignancy derived cell lines and a pediatric B-ALL were used to demonstrate pharmacological efficacy. Results: Non-selective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform specific HDACi indicated that targeting HDAC1-3 with class I HDAC specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo while it was far less effective against other B-cell derived malignancies. Conclusions: Here we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL.