组蛋白去乙酰化酶抑制剂与AML1-ETO阳性急性髓细胞白血病的研究进展

Research progress of histon deacetylase inhibitors in AML1-ETO positive acute myeloid leukemia

第8号与第21号染色体发生易位，t（8；21）（q22；q22）可使位于第21号染色体的急性髓细胞白血病（AML）1基因与位于第8号染色体的ETO基因融合，形成AML1-ETO融合基因。AML1-ETO能够募集mSin3／N—CoR／sMART／HDAC共抑制复合物至AMLl靶基因的启动子区，使白细胞介素（IL）-3、粒-巨噬细胞集落刺激因子（GM—CSF）等与造血干细胞分化有关的基因及抑癌基因失活，进而导致白血病发生。组蛋白去乙酰化酶抑制剂（HDACI）通过组蛋白乙酰化、染色质重塑，可使AML1-ETO目的基因恢复表达、降解AML1-ETO融合蛋白等发挥抗白血病作用，同时选择性作用于AML1-ETO阳性细胞。目前，HDACI与DNA去甲基化药物、糖皮质激素类药物、热休克蛋白（HSP）-90抑制剂及三氧化二砷（AT0）联合应用治疗AML1-ETO阳性AML还在探索阶段。笔者拟就HDACI对AML1ETO融合蛋白及其目的基因的作用，以及HDACI联合用药在AML1-ETO阳性AML治疗方面的作用机制进行综述。

The t（8;21） （q22;q22） results in fusion of acute myeloid leukemia （AML） I gene on chromosome 21 and ETO gene on chromosome 8, and produces AML1-ETO fusion gene, which plays a critical role in leukemogenesis by recruiting mSin3/N-CoR/SMART/HDACs corepressor complex to promoter of AML1 target genes including interluekin （IL）-3 and granulocyte macrophage-colony stimulating factor （GM-CSF） related to differentiation of hematopoietic stem cells and inactivating tumor suppressor genes. Histon deacetylase inhibitors （HDACI） reexpress silenced suppressor genes through regulation of histone acetylation and chromatin remodeling. Moreover, some of HDACI are able to degrade AML1-ETO fusion and play a selective role in AML1-ETO positive AML. The combinations of HDACI with DNA hypomethylated medicine, glucocorticoid, heat shock protein （HSP）-90 inhibitor and arsenic trioxide （ATO） are explored for the therapy of AML1-ETO positive AML. Herein, we discuss the effect and mechanism of HDACI on fusion protein of the AML1-ETO, and its target genes, as well as the mechanism in treatment of AML1-ETO positive AML with HDACI.