Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors
Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors
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DOI：
10.1182/blood-2013-03-488114
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发表时间：
2014-02-27
期刊：
影响因子：
20.3
通讯作者：
Johnstone, Ricky W.
中科院分区：
文献类型：
--
作者：
Bots, Michael;Verbrugge, Inge;Johnstone, Ricky W.
表观遗传修饰酶如组蛋白脱乙酰酶（HDAC）、p300和PRMT 1被AML 1/ETO（t（8;21）急性髓性白血病（AML）的致病蛋白）募集，为靶向这些酶治疗这种疾病提供了强有力的分子基础。尽管早期临床评估表明HDAC抑制剂（HDACis）治疗可能对t（8;21）AML患者有效，但尚未进行严格的临床前研究以确定可能决定治疗反应的分子和生物学事件。使用由AML 1/ETO 9a（A/E9 a）表达驱动的AML小鼠模型，我们证明了用HDACi帕比司他治疗携带t（8;21）AML的小鼠可引起稳健的抗白血病应答，该应答不需要功能性p53，也不需要激活常规凋亡途径。帕比司他通过A/E9 a的蛋白酶体降解触发终末骨髓分化。重要的是，条件性A/E9 a缺失表型模拟了帕比司他和其他HDAC的作用，表明A/E9 a的去稳定化对于这些药物的抗白血病活性至关重要。
Epigenetic modifying enzymes such as histone deacetylases (HDACs), p300, and PRMT1 are recruited by AML1/ETO, the pathogenic protein for t(8;21) acute myeloid leukemia (AML), providing a strong molecular rationale for targeting these enzymes to treat this disease. Although early phase clinical assessment indicated that treatment with HDAC inhibitors (HDACis) may be effective in t(8;21) AML patients, rigorous preclinical studies to identify the molecular and biological events that may determine therapeutic responses have not been performed. Using an AML mouse model driven by expression of AML1/ETO9a (A/E9a), we demonstrated that treatment of mice bearing t(8;21) AML with the HDACi panobinostat caused a robust antileukemic response that did not require functional p53 nor activation of conventional apoptotic pathways. Panobinostat triggered terminal myeloid differentiation via proteasomal degradation of A/E9a. Importantly, conditional A/E9a deletion phenocopied the effects of panobinostat and other HDACis, indicating that destabilization of A/E9a is critical for the antileukemic activity of these agents.