Differentiation therapy of acute myeloid leukemia: past, present and future
Differentiation therapy of acute myeloid leukemia: past, present and future
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DOI：
10.1097/moh.0b013e3283257aee
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发表时间：
2009-03-01
影响因子：
3.2
通讯作者：
Waxman, Samuel
中科院分区：
文献类型：
--
作者：
Petrie, Kevin;Zelent, Arthur;Waxman, Samuel
综述目的自 20 世纪 70 年代以来，分化治疗的概念一直被视为治疗急性髓系白血病 (AML) 和其他癌症的一种有前景的革命性方法。然而，分化疗法自20世纪80年代末才在临床上取得成功，并且仅针对AML的一种亚型，即急性早幼粒细胞白血病（APL）。全反式视黄酸 (ATRA) 和三氧化二砷均可诱导进行性多灶性白质脑病/视黄酸受体癌蛋白的降解，与化疗相结合是目前公认的 APL 治疗方法，为临床肿瘤学中的分化治疗提供了潜在的范例。最近的研究结果我们已经开始了解为什么 ATRA 无法诱导 AML 分化。迄今为止已确定的根本原因与无法靶向去除致白血病融合蛋白、ATRA 信号通路相关基因的异常表观遗传调控以及干扰视黄酸受体功能的因素的存在有关。 总结在这里，我们研究了 APL 对基于 ATRA 的分化治疗的敏锐敏感性尚未扩展到其他 AML 亚型的原因。还将分析当前针对 AML 的基于分化的组合方法。最后，我们将评估新策略、高通量筛选和功能基因组学的潜力，以发现新的基于分化的 AML 疗法。
Purpose of reviewSince the 1970s, the concept of differentiation therapy has been viewed as a promising and revolutionary approach for the treatment of acute myeloid leukemia (AML) and other cancers. However, the successful clinical application of differentiation therapy has only been realized since the late 1980s and only in one subtype of AML, acute promyelocytic leukemia (APL). The use of all-trans-retinoic acid (ATRA) and arsenic trioxide, both of which induce degradation of the progressive multifocal leukoencephalopathy/retinoic acid receptor a oncoprotein, in combination with chemotherapy is currently the accepted treatment of APL, presenting a potential paradigm for differentiation therapy in clinical oncology.Recent findingsWe have begun to understand why ATRA fails to induce differentiation in AML. The underlying reasons identified thus far are associated with an inability to target the removal of leukemogenic fusion proteins, aberrant epigenetic regulation of genes involved in the ATRA signaling pathway and the presence of factors that interfere with proper retinoic acid receptor a function.SummaryHere, we examine the reasons why the exquisite sensitivity of APL to ATRA-based differentiation therapy has not been extended to other of AML subtypes. Current differentiation-based combinatorial approaches to target AML will also be analyzed, Finally, we will evaluate the potential of novel strategies, high-throughput screening, and functional genomics to uncover new differentiation-based therapies for AML.