Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; University of Virginia Cancer Center, Charlottesville, VA, United States of America.
Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; University of Virginia Cancer Center, Charlottesville, VA, United States of America.
Blood Rev. 2022 Sep;55:100950. doi: 10.1016/j.blre.2022.100950. Epub 2022 Apr 9.
Acute myeloid leukemia (AML) is an aggressive, heterogenous malignancy characterized by clonal expansion of bone marrow-derived myeloid progenitor cells. While our current understanding of the molecular and genomic landscape of AML has evolved dramatically and opened avenues for molecularly targeted therapeutics to improve upon standard intensive induction chemotherapy, curative treatments are elusive, particularly in older patients. Responses to current AML treatments are transient and incomplete, necessitating the development of novel treatment strategies to improve outcomes. To this end, harnessing the power of bioactive sphingolipids to treat cancer shows great promise. Sphingolipids are involved in many hallmarks of cancer of paramount importance in AML. Leukemic blast survival is influenced by cellular levels of ceramide, a bona fide pro-death molecule, and its conversion to signaling molecules such as sphingosine-1-phosphate and glycosphingolipids. Preclinical studies demonstrate the efficacy of therapeutics that target dysregulated sphingolipid metabolism as well as their combinatorial synergy with clinically-relevant therapeutics. Thus, increased understanding of sphingolipid dysregulation may be exploited to improve AML patient care and outcomes. This review summarizes the current knowledge of dysregulated sphingolipid metabolism in AML, evaluates how pro-survival sphingolipids promote AML pathogenesis, and discusses the therapeutic potential of targeting these dysregulated sphingolipid pathways.
急性髓系白血病 (AML) 是一种侵袭性、异质性恶性肿瘤，其特征是骨髓源性髓系祖细胞的克隆性扩张。虽然我们对 AML 的分子和基因组景观的理解已经有了显著的发展，并为分子靶向治疗开辟了途径，以提高标准强化诱导化疗的效果，但治愈方法仍然难以捉摸，尤其是在老年患者中。目前 AML 治疗的反应是短暂和不完全的，需要开发新的治疗策略来改善预后。为此，利用生物活性神经鞘脂治疗癌症显示出巨大的潜力。神经鞘脂参与了许多癌症的重要标志，在 AML 中也具有重要意义。白血病细胞的存活受到神经酰胺（一种真正的促死亡分子）的细胞水平的影响，以及其转化为信号分子，如鞘氨醇-1-磷酸和糖鞘脂。临床前研究表明，靶向失调的神经鞘脂代谢的治疗方法以及它们与临床相关治疗方法的组合协同作用具有疗效。因此，增加对神经鞘脂失调的理解可能被用来改善 AML 患者的护理和结果。这篇综述总结了 AML 中失调的神经鞘脂代谢的现有知识，评估了促生存神经鞘脂如何促进 AML 的发病机制，并讨论了靶向这些失调的神经鞘脂途径的治疗潜力。
