McGraw Kathy L, Larson Daniel R
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20872; Immune Deficiencies-Cellular Therapy Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20872; Myeloid Malignancies Program, National Institutes of Health, Bethesda, MD, 20872.
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20872; Immune Deficiencies-Cellular Therapy Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20872; Myeloid Malignancies Program, National Institutes of Health, Bethesda, MD, 20872.
Semin Hematol. 2024 Dec;61(6):470-478. doi: 10.1053/j.seminhematol.2024.11.004. Epub 2024 Nov 22.
The Myelodysplastic Syndromes (MDS) are heterogeneous stem cell malignancies clinically characterized by bone marrow dysplasia, peripheral blood cytopenias, and a high risk for transformation to acute myeloid leukemia. In early stages of disease, differentiation defects and maturation blocks result in deficient hematopoiesis. In higher risk disease, unrestricted proliferation of immature blast cells leads to leukemogenesis. Disease pathogenesis can be attributed to many factors including chronic inflammation that is driven in part by commonly found somatic gene mutations (SGM) fostering expansion of malignant clones while suppressing normal hematopoiesis. Cellular metabolism that both directly and indirectly regulates hematopoietic stem cell (HSC) fate, is intimately connected to the immune system, is altered by MDS somatic gene mutations and is likely is a major contributor to disease pathophysiology. Despite this likely role in pathobiology, there is an underwhelming depth of literature on the subject and the precise metabolic dysregulations in these myeloid malignancies have yet to be fully delineated. In this review, we will provide a general overview of several major metabolic processes and how each directs HSC fate, provide a summary of metabolic studies in MDS, discuss how common SGM and inflammation influence metabolic pathways to drive bone marrow failure, and end with a discussion of standards of care and how these should be carefully considered in the context of metabolic dysregulation.
骨髓增生异常综合征（MDS）是一类异质性干细胞恶性肿瘤，临床特征为骨髓发育异常、外周血细胞减少以及转化为急性髓系白血病的高风险。在疾病早期，分化缺陷和成熟阻滞导致造血功能不足。在高危疾病中，未成熟原始细胞的无限制增殖导致白血病发生。疾病发病机制可归因于多种因素，包括慢性炎症，其部分由常见的体细胞基因突变（SGM）驱动，这些突变促进恶性克隆的扩增，同时抑制正常造血。细胞代谢直接和间接调节造血干细胞（HSC）的命运，与免疫系统密切相关，因MDS体细胞基因突变而改变，并且可能是疾病病理生理学的主要促成因素。尽管在病理生物学中可能发挥这一作用，但关于该主题的文献深度不足，这些髓系恶性肿瘤中精确的代谢失调尚未完全阐明。在本综述中，我们将概述几个主要的代谢过程以及每个过程如何指导HSC命运，总结MDS中的代谢研究，讨论常见的SGM和炎症如何影响代谢途径以导致骨髓衰竭，并最后讨论治疗标准以及在代谢失调的背景下应如何仔细考虑这些标准。
