文章：

髓系恶性肿瘤的诱导分化治疗：超越细胞毒性的新策略

Differentiation therapy for myeloid malignancies: beyond cytotoxicity

原文发布日期：2021-12-04

DOI: 10.1038/s41408-021-00584-3

类型: Review Article

开放获取: 是

英文摘要：

Blocked cellular differentiation is a central pathologic feature of the myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Treatment regimens promoting differentiation have resulted in incredible cure rates in certain AML subtypes, such as acute promyelocytic leukemia. Over the past several years, we have seen many new therapies for MDS/AML enter clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, fms-like kinase 3 (FLT3) inhibitors, and lenalidomide for deletion 5q (del5q) MDS. Despite not being developed with the intent of manipulating differentiation, induction of differentiation is a major mechanism by which several of these novel agents function. In this review, we examine the new therapeutic landscape for these diseases, focusing on the role of hematopoietic differentiation and the impact of inflammation and aging. We review how current therapies in MDS/AML promote differentiation as a part of their therapeutic effect, and the cellular mechanisms by which this occurs. We then outline potential novel avenues to achieve differentiation in the myeloid malignancies for therapeutic purposes. This emerging body of knowledge about the importance of relieving differentiation blockade with anti-neoplastic therapies is important to understand how current novel agents function and may open avenues to developing new treatments that explicitly target cellular differentiation. Moving beyond cytotoxic agents has the potential to open new and unexpected avenues in the treatment of myeloid malignancies, hopefully providing more efficacy with reduced toxicity.
 

摘要翻译： 

细胞分化阻滞是髓系恶性肿瘤——骨髓增生异常综合征（MDS）和急性髓系白血病（AML）的核心病理特征。促进分化的治疗方案已在某些AML亚型（如急性早幼粒细胞白血病）中取得显著治愈率。过去几年间，多种针对MDS/AML的新疗法已进入临床实践，包括表观遗传治疗（如5-氮杂胞苷）、异柠檬酸脱氢酶（IDH）抑制剂、FMS样酪氨酸激酶3（FLT3）抑制剂以及用于5q缺失（del5q）型MDS的来那度胺。尽管这些新型药物并非以调控分化为初始研发目标，但诱导分化已成为其发挥疗效的关键机制。本文综述中，我们审视了这些疾病的新治疗格局，重点关注造血分化的作用以及炎症与衰老的影响。我们探讨当前MDS/AML疗法如何通过促进分化实现治疗效果及其细胞机制，进而展望为治疗目的在髓系恶性肿瘤中实现分化的潜在新途径。理解通过抗肿瘤疗法解除分化阻滞的重要性，对于认识现有新型药物的作用机制至关重要，并可能为开发直接靶向细胞分化的新疗法开辟道路。超越传统细胞毒性药物的治疗策略，有望为髓系恶性肿瘤治疗开拓崭新而意想不到的途径，在提升疗效的同时降低治疗毒性。

原文链接：

Differentiation therapy for myeloid malignancies: beyond cytotoxicity