Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology over the past decade. Recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies. The discovery of drugs that promote apoptosis in leukemic cells has translated to encouraging activity in clinical trials. B-cell lymphoma (BCL)-2 inhibition has been at the center of drug development efforts to target apoptosis in AML. Remarkable clinical success with venetoclax has revolutionized the ways we treat hematological malignancies. Several landmark trials have demonstrated the potent antitumor activity of venetoclax, and it is now frequently combined with traditional cytotoxic agents to treat AML. However, resistance to BCL-2 inhibition is emerging, and alternative strategies to address resistance mechanisms have become an important focus of research. A number of clinical trials are now underway to investigate a plurality of novel agents that were shown to overcome resistance to BCL-2 inhibition in preclinical models. Some of the most promising data come from studies on drugs that downregulate myeloid cell leukemia (MCL)-1, such as cyclin-dependent kinases (CDK) inhibitors. Furthermore, innovative approaches to target apoptosis via extrinsic pathways and p53 regulation have added new cytotoxic agents to the arsenal, including drugs that inhibit inhibitor of apoptosis protein (IAP) family proteins and murine double minute 2 (MDM2). This review provides a perspective on past and current treatment strategies harnessing various mechanisms of apoptosis to target AML and highlights some important promising treatment combinations in development.

中文翻译：

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针对急性髓细胞性白血病的细胞凋亡：Venetoclax及其它抑制剂对BCL-2抑制作用的现状和未来方向。

尽管我们在过去十年中对潜在的癌症生物学有了新的了解，但急性髓细胞性白血病（AML）是造血系统疾病，仍然是一种治疗挑战。分子靶向的最新发展已显示出在治疗白血病方面有希望的结果，为新型治疗策略铺平了道路。促进白血病细胞凋亡的药物的发现已转化为在临床试验中令人鼓舞的活性。B细胞淋巴瘤（BCL）-2抑制一直是靶向AML中细胞凋亡的药物开发工作的中心。Venetoclax在临床上的巨大成功彻底改变了我们治疗血液系统恶性肿瘤的方法。几个具有里程碑意义的试验证明了委内瑞拉具有很强的抗肿瘤活性，并且现在经常与传统的细胞毒剂联合使用来治疗AML。然而，对BCL-2抑制的抗药性正在出现，解决抗药性机制的替代策略已成为研究的重要重点。目前正在进行许多临床试验，以研究多种新药，这些新药在临床前模型中显示可克服对BCL-2抑制的抗性。一些最有希望的数据来自对下调髓样细胞白血病（MCL）-1的药物的研究，例如细胞周期蛋白依赖性激酶（CDK）抑制剂。此外，通过外在途径和p53调控来靶向凋亡的创新方法已为军火库增加了新的细胞毒性剂，包括抑制凋亡蛋白（IAP）家族蛋白抑制剂和鼠双分2（MDM2）的药物。