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Supplementary Table S1-S3 Legends and Supplementary Figure S1-S6 Legends. Legends for supplementary tables S1-S3 and supplementary figures S1-S6 which support data in the manuscript, but could not be included due to space constraints.

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 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. Clin Cancer Res; 21(10); 2348–58. ©2015 AACR.

Supplementary Tables S1-S3 and Supplementary Figures S1-S6. Table S1 - EC50 values for B-cell malignancies treated with HDAC inhibitors of varying isoform selectivity Table S2 - EC50 values for B-ALL cell line treated with a panel of HDAC inhibitors Table S3 - statistics for cell growth assay in Figure 3 Figure S1 - In vitro survival and PD for B-ALL cells treated with LAQ824 Figure S2 - Western analyses of B-ALL cells treated with MS275 Figure S3 - Western blots, cell growth and cell cycle analysis for B-ALL cells transduced with HDAC1,2, or 3 specific shRNA Figure S4 - Western analyses, cell growth and survival of B-ALL cell treated with Merck60 Figure S5 - Survival and western blots for B-ALL cells treated with HDACi with an apoptosis inhibitor. Figure S6 - Western blots to show DNA damage caused by HDACi or doxorubicin in Merck60 insensitive multiple myeloma cell lines.