Selective inhibition of HDAC1 and HDAC2 as a potential therapeutic option for B-ALL Journal Article
| Authors: | Stubbs, M. C.; Kim, W.; Bariteau, M.; Davis, T.; Vempati, S.; Minehart, J.; Witkin, M.; Qi, J.; Krivtsov, A. V.; Bradner, J. E.; Kung, A. L.; Armstrong, S. A. |
| Article Title: | Selective inhibition of HDAC1 and HDAC2 as a potential therapeutic option for B-ALL |
| Abstract: | 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. Isoformspecific 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 pharmacologic efficacy. Results: Nonselective 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, whereas 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. ©2015 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 21 |
| Issue: | 10 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2015-05-15 |
| Start Page: | 2348 |
| End Page: | 2358 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-14-1290 |
| PROVIDER: | scopus |
| PMCID: | PMC4433811 |
| PUBMED: | 25688158 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
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