Warrell R P, He L Z, Richon V, Calleja E, Pandolfi P P
Department of Medicine, Memorial Sloan-Kettering Cancer Center, and the Cornell University Medical College, New York, NY 10021, USA.
J Natl Cancer Inst. 1998 Nov 4;90(21):1621-5. doi: 10.1093/jnci/90.21.1621.
Acetylation of DNA-associated histones is linked to activation of gene transcription, whereas histone deacetylation is associated with transcriptional repression. Recent studies have shown that inhibitors of histone deacetylases can relieve transcriptional repression caused by the products of certain oncogenes. We tested whether these findings could be applied clinically to a patient with highly resistant acute promyelocytic leukemia.
A patient who had experienced multiple relapses was treated with all-trans-retinoic acid alone and in combination with sodium phenylbutyrate, an inhibitor of histone deacetylases. Immunohistochemistry and western blot analysis were used to assay for histone hyperacetylation in mononuclear cells from the patient's blood and bone marrow. Marrow mononuclear cells and reverse transcription-polymerase chain reaction (RT-PCR) analysis of messenger RNA encoded by the PML/RAR-alpha oncogene were used to assess minimal residual disease.
The patient proved clinically resistant to treatment with all-trans-retinoic acid alone. However, 23 days after sodium phenylbutyrate was added to the treatment regimen, visible leukemic cells had been eliminated from her bone marrow, and she achieved a complete clinical and cytogenetic remission shortly thereafter. With a second treatment course, analysis for minimal residual disease by RT-PCR proved negative. Immunofluorescence and western blot analysis showed that phenylbutyrate caused a time-dependent increase in histone acetylation in blood and bone marrow mononuclear cells.
Clinical treatment with an inhibitor of histone deacetylase induces histone hyperacetylation in target cells and may restore sensitivity to the anti-leukemic effects of all-trans-retinoic acid in acute promyelocytic leukemia. Similar therapy may prove useful in other neoplastic diseases that are associated with oncogenic repression of gene transcription due to recruitment of histone deacetylases.
与DNA相关的组蛋白乙酰化与基因转录激活有关，而组蛋白去乙酰化则与转录抑制相关。最近的研究表明，组蛋白去乙酰化酶抑制剂可缓解某些癌基因产物所致的转录抑制。我们测试了这些发现是否能在临床上应用于一名具有高度耐药性的急性早幼粒细胞白血病患者。
一名经历多次复发的患者接受了全反式维甲酸单药治疗以及与组蛋白去乙酰化酶抑制剂苯丁酸钠联合治疗。采用免疫组织化学和蛋白质印迹分析来检测患者血液和骨髓单个核细胞中的组蛋白高乙酰化。采用骨髓单个核细胞以及对PML/RAR-α癌基因编码的信使核糖核酸进行逆转录聚合酶链反应（RT-PCR）分析来评估微小残留病。
该患者对单独使用全反式维甲酸治疗在临床上表现出耐药。然而，在治疗方案中加入苯丁酸钠23天后，其骨髓中可见的白血病细胞已被清除，此后不久她实现了完全的临床和细胞遗传学缓解。在第二个疗程中，通过RT-PCR分析微小残留病结果为阴性。免疫荧光和蛋白质印迹分析表明，苯丁酸钠可使血液和骨髓单个核细胞中的组蛋白乙酰化呈时间依赖性增加。
使用组蛋白去乙酰化酶抑制剂进行临床治疗可诱导靶细胞中的组蛋白高乙酰化，并可能恢复急性早幼粒细胞白血病对全反式维甲酸抗白血病作用的敏感性。类似的疗法可能对其他因组蛋白去乙酰化酶募集导致基因转录致癌性抑制相关的肿瘤性疾病有用。
