Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors
Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors
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DOI：
10.1038/sj.leu.2403910
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发表时间：
2005-10-01
期刊：
影响因子：
11.4
通讯作者：
Turner, BM
中科院分区：
文献类型：
--
作者：
Bradbury, C;Khanim, F;Turner, BM
组蛋白去乙酰化酶抑制剂（HDIs）是一类具有显著抗白血病活性的新药。为了探索急性髓性白血病（AML）中疾病特异性HDI活性的机制，我们已经表征了组蛋白去乙酰化酶家族的所有18个成员在原发性AML原始细胞和四种对照细胞类型中的表达，即来自脐带的CD34+祖细胞，静止或循环（培养后），来自GCSF刺激的成人供体和外周血单核细胞的循环CD34+祖细胞。与所有对照相比，AML样品中只有SIRT1持续过表达（> 2倍），而HDAC6相对于成人细胞过表达，而不是新生细胞。HDAC5和SIRT4始终表达不足。AML母细胞和细胞系，暴露于HDIs的文化，显示组蛋白超乙酰化和，出乎意料的是，特定的H3赖氨酸4的超甲基化。这种处理还调节了HDAC表达的模式，在所有测试的髓样细胞中以及在所有抑制剂（丙戊酸盐、丁酸盐、TSA、SAHA）的情况下都强烈诱导HDAC 11，并且更少、更有选择性地诱导HDAC 9和SIRT 4。AML中HDAC表达的独特模式及其对HDI的反应与基于HDI的治疗策略的开发相关，并可能有助于观察到的临床反应模式和耐药性的发展。
Histone deacetylase inhibitors (HDIs) are a new class of drugs with significant antileukemic activity. To explore mechanisms of disease-specific HDI activity in acute myeloid leukaemia (AML), we have characterised expression of all 18 members of the histone deacetylase family in primary AML blasts and in four control cell types, namely CD34+ progenitors from umbilical cord, either quiescent or cycling (post-culture), cycling CD34+ progenitors from GCSF-stimulated adult donors and peripheral blood mononuclear cells. Only SIRT1 was consistently overexpressed (> 2 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells. HDAC5 and SIRT4 were consistently underexpressed. AML blasts and cell lines, exposed to HDIs in culture, showed both histone hyperacetylation and, unexpectedly, specific hypermethylation of H3 lysine 4. Such treatment also modulated the pattern of HDAC expression, with strong induction of HDAC11 in all myeloid cells tested and with all inhibitors (valproate, butyrate, TSA, SAHA), and lesser, more selective, induction of HDAC9 and SIRT4. The distinct pattern of HDAC expression in AML and its response to HDIs is of relevance to the development of HDI-based therapeutic strategies and may contribute to observed patterns of clinical response and development of drug resistance.