Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL.
Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL.
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DOI：
10.1158/1078-0432.ccr-14-1290
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发表时间：
2015-05-15
期刊：
影响因子：
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通讯作者：
Armstrong SA
中科院分区：
文献类型：
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作者：
Stubbs MC;Kim W;Bariteau M;Davis T;Vempati S;Minehart J;Witkin M;Qi J;Krivtsov AV;Bradner JE;Kung AL;Armstrong SA
组蛋白去乙酰化酶抑制剂（HDACi）最近已成为针对血液恶性肿瘤表观遗传机制的有效疗法。一种这样的血液恶性肿瘤，B细胞急性淋巴细胞白血病（B-ALL），可能高度依赖于白血病发展和维持的表观遗传调控，因此对靶向表观遗传机制的小分子抑制剂敏感。测试了一组B-ALL细胞系对HDACi的敏感性，其具有不同的同种型敏感性。同种型特异性shRNA被用于进一步验证HDAC作为B-ALL中的相关治疗靶标。使用B细胞恶性肿瘤衍生细胞系和儿科B-ALL的小鼠异种移植物来证明药理学功效。非选择性HDAC抑制剂对一组B-ALL细胞系以及异种移植的人白血病患者样品具有细胞毒性。同种型特异性HDACi的评估表明，用I类HDAC特异性抑制剂靶向HDAC 1 -3足以抑制B-ALL细胞系的生长。此外，shRNA介导的HDAC 1或HDAC 2的敲低导致这些细胞中的生长抑制。然后，我们评估了一种仅特异性抑制HDAC 1和HDAC 2的化合物。该化合物在体外和体内抑制B-ALL细胞系的生长并诱导细胞凋亡，而对其他B细胞来源的恶性肿瘤的有效性要低得多。在这里，我们表明HDAC抑制剂是B-ALL的潜在治疗选择，并且HDAC 1和HDAC 2的更特异性抑制剂可能对B-ALL患者有治疗作用。
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. 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. 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. 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.