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.

细胞分化受阻是髓系恶性肿瘤、骨髓增生异常综合征 (MDS) 和急性髓性白血病 (AML) 的主要病理特征。促进分化的治疗方案在某些 AML 亚型（如急性早幼粒细胞白血病）中取得了令人难以置信的治愈率。在过去的几年里，我们看到许多 MDS/AML 的新疗法进入临床实践，包括表观遗传疗法（如 5-阿扎胞苷）、异柠檬酸脱氢酶 (IDH) 抑制剂、fms 样激酶 3 (FLT3) 抑制剂和来那度胺用于删除 5q (del5q) MDS。尽管不是为了操纵分化而开发的，但诱导分化是这些新型药物中的一些发挥作用的主要机制。在这篇综述中，我们研究了这些疾病的新治疗前景，重点关注造血分化的作用以及炎症和衰老的影响。我们回顾了 MDS/AML 的当前疗法如何促进分化作为其治疗效果的一部分，以及发生这种情况的细胞机制。然后，我们概述了潜在的新途径，以实现骨髓恶性肿瘤的分化以达到治疗目的。这种关于用抗肿瘤疗法缓解分化阻断的重要性的新兴知识体系对于了解当前的新型药物如何发挥作用很重要，并可能为开发明确针对细胞分化的新疗法开辟道路。超越细胞毒性药物有可能在治疗骨髓恶性肿瘤方面开辟新的和意想不到的途径，有望提供更高的疗效和更低的毒性。