Department of Internal Medicine I, University Hospital Carl Gustav Carus, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
German Cancer Consortium (DKTK), CHOICE Consortium, Partner Sites Dresden/Munich/Frankfurt/Mainz, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Leukemia. 2024 May;38(5):936-946. doi: 10.1038/s41375-024-02226-6. Epub 2024 Mar 21.
Clonal hematopoiesis (CH) defines a premalignant state predominantly found in older persons that increases the risk of developing hematologic malignancies and age-related inflammatory diseases. However, the risk for malignant transformation or non-malignant disorders is variable and difficult to predict, and defining the clinical relevance of specific candidate driver mutations in individual carriers has proved to be challenging. In addition to the cell-intrinsic mechanisms, mutant cells rely on and alter cell-extrinsic factors from the bone marrow (BM) niche, which complicates the prediction of a mutant cell's fate in a shifting pre-malignant microenvironment. Therefore, identifying the insidious and potentially broad impact of driver mutations on supportive niches and immune function in CH aims to understand the subtle differences that enable driver mutations to yield different clinical outcomes. Here, we review the changes in the aging BM niche and the emerging evidence supporting the concept that CH can progressively alter components of the local BM microenvironment. These alterations may have profound implications for the functionality of the osteo-hematopoietic niche and overall bone health, consequently fostering a conducive environment for the continued development and progression of CH. We also provide an overview of the latest technology developments to study the spatiotemporal dependencies in the CH BM niche, ideally in the context of longitudinal studies following CH over time. Finally, we discuss aspects of CH carrier management in clinical practice, based on work from our group and others.
克隆性造血 (CH) 定义了一种主要发生在老年人中的前恶性状态，增加了发生血液系统恶性肿瘤和与年龄相关的炎症性疾病的风险。然而，恶性转化或非恶性疾病的风险是可变的，难以预测，并且证明在个体携带者中定义特定候选驱动突变的临床相关性具有挑战性。除了细胞内在机制外，突变细胞还依赖于骨髓 (BM) 龛位的细胞外因子并改变这些因子，这使得在不断变化的前恶性微环境中预测突变细胞的命运变得复杂。因此，确定驱动突变对 CH 中支持性龛位和免疫功能的潜在广泛影响旨在了解使驱动突变产生不同临床结果的细微差异。在这里，我们回顾了衰老 BM 龛位的变化以及支持 CH 可逐渐改变局部 BM 微环境成分的新概念的出现证据。这些改变可能对成骨-造血龛位的功能和整体骨骼健康产生深远影响，从而为 CH 的持续发展和进展提供有利环境。我们还概述了研究 CH BM 龛位时空依赖性的最新技术发展，理想情况下是在随着时间的推移对 CH 进行纵向研究的背景下。最后，我们根据我们小组和其他小组的工作讨论了 CH 携带者在临床实践中的管理方面。
