Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis
Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis
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DOI：
10.1038/s41375-018-0047-7
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发表时间：
2018-09-01
期刊：
影响因子：
11.4
通讯作者：
Damm, Frederik
中科院分区：
文献类型：
--
作者：
Arends, Christopher Maximilian;Galan-Sousa, Joel;Damm, Frederik
不确定潜能的克隆性造血（CHIP）以与年龄相关的方式发生，并与血液学癌症、动脉粥样硬化疾病的风险增加和总生存期缩短相关。关于细胞起源、造血分化树内克隆突变的再分配模式及其在进化压力下的动态，我们知之甚少。使用靶向测序，在437名老年人中的121名（27.7%）中鉴定出CHIP。在6个外周血细胞组分中研究了91个突变的变异等位基因频率（VAF）。与B细胞或T细胞相比，单核细胞、粒细胞和NK细胞中的VAF显著更高。在所有具有可用骨髓材料的情况下，可在Lin（-）CD 34（+）CD 38（-）HSC中鉴定突变，随后扩增为髓样致敏祖细胞。在22例接受（放射）化疗的实体癌患者中，在121个时间点对32个突变进行的纵向研究确定了13/32个突变的相对VAF变化至少为50%。DNMT 3A的VAF在12/13例中稳定（P < .001）。具有DNMT 3A以外的克隆突变的癌症患者需要更频繁地输注红细胞和减少剂量。我们的研究结果提供了新的见解克隆突变的细胞分布，化疗下的动力学，并主张系统分析癌症患者的CHIP。
Clonal hematopoiesis of indeterminate potential (CHIP) occurs in an age-related manner and associates with an increased risk of hematologic cancer, atherosclerotic disease, and shorter overall survival. Little is known about the cell of origin, repartition patterns of clonal mutations within the hematopoietic differentiation tree, and its dynamics under evolutionary pressure. Using targeted sequencing, CHIP was identified in 121 out of 437 elderly individuals (27.7%). Variant allele frequencies (VAFs) of 91 mutations were studied in six peripheral blood cell fractions. VAFs were significantly higher in monocytes, granulocytes, and NK-cells compared to B- or T cells. In all cases with available bone marrow material, mutations could be identified in Lin(-)CD34(+)CD38(-) HSCs with subsequent expansion to myeloid primed progenitors. In 22 patients with solid cancer receiving (radio-)chemotherapy, longitudinal study of 32 mutations at 121 time points identified relative VAF changes of at least 50% in 13/32 mutations. VAFs of DNMT3A, were stable in 12/13 cases (P < .001). Cancer patients with a clonal mutation other than DNMT3A required more often red blood cell transfusions and dose reductions. Our results provide novel insights into cellular distribution of clonal mutations, their dynamics under chemotherapy, and advocate for systematic analyses for CHIP in cancer patients.