人类骨髓中造血克隆的空间分布图

IF 11.5 Q1 HEMATOLOGY Blood Cancer Discovery Pub Date : 2024-05-01 DOI:10.1158/2643-3230.BCD-23-0110
Andrew L Young, Hannah C Davis, Maggie J Cox, Tyler M Parsons, Samantha C Burkart, Diane E Bender, Lulu Sun, Stephen T Oh, Grant A Challen
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摘要

克隆性造血(CH)是指没有造血功能障碍的个体造血细胞中体细胞突变细胞的扩增。大型克隆造血(即变异等位基因比例大于 2%)易导致血液恶性肿瘤,但几乎所有中年人体内都能检测到较低水平的克隆造血。先前的研究已广泛描述了外周血中 CH 的特征,但人类骨髓中造血克隆的空间分布在很大程度上还未被描述。为了在这一层面了解 CH,我们开发了一种空间感知体细胞突变分析方法,并对一名多发性红细胞症患者的骨髓进行了特征描述。我们发现了体细胞突变在造血区的复杂克隆分布、体细胞突变对特定造血细胞亚群的限制以及这些克隆在骨髓中的空间限制。这一原理证明为回答有关骨髓中CH空间组织和驱动CH扩展及恶性转化的因素的基本问题铺平了道路。
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Spatial Mapping of Hematopoietic Clones in Human Bone Marrow.

Clonal hematopoiesis (CH) is the expansion of somatically mutated cells in the hematopoietic compartment of individuals without hematopoietic dysfunction. Large CH clones (i.e., >2% variant allele fraction) predispose to hematologic malignancy, but CH is detected at lower levels in nearly all middle-aged individuals. Prior work has extensively characterized CH in peripheral blood, but the spatial distribution of hematopoietic clones in human bone marrow is largely undescribed. To understand CH at this level, we developed a method for spatially aware somatic mutation profiling and characterized the bone marrow of a patient with polycythemia vera. We identified the complex clonal distribution of somatic mutations in the hematopoietic compartment, the restriction of somatic mutations to specific subpopulations of hematopoietic cells, and spatial constraints of these clones in the bone marrow. This proof of principle paves the way to answering fundamental questions regarding CH spatial organization and factors driving CH expansion and malignant transformation in the bone marrow.

Significance: CH occurs commonly in humans and can predispose to hematologic malignancy. Although well characterized in blood, it is poorly understood how clones are spatially distributed in the bone marrow. To answer this, we developed methods for spatially aware somatic mutation profiling to describe clonal heterogeneity in human bone marrow. See related commentary by Austin and Aifantis, p. 139.

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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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