Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History.
Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History.
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DOI：
10.1158/2159-8290.cd-21-0276
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发表时间：
2021-12-01
期刊：
影响因子：
28.2
通讯作者：
Wu CJ
中科院分区：
文献类型：
--
作者：
Penter L;Gohil SH;Lareau C;Ludwig LS;Parry EM;Huang T;Li S;Zhang W;Livitz D;Leshchiner I;Parida L;Getz G;Rassenti LZ;Kipps TJ;Brown JR;Davids MS;Neuberg DS;Livak KJ;Sankaran VG;Wu CJ
虽然癌症在疾病进展期间和响应于治疗而演变，但由于缺乏标记体内个体克隆的一致条形码，在人类中仍然难以研究时间动力学。我们采用转座酶可接近染色质的线粒体单细胞测定和测序，对来自9名慢性淋巴细胞白血病（CLL）患者的163，279个细胞进行了分析，并利用线粒体DNA（mtDNA）突变作为癌症克隆的天然遗传标记。我们观察到稳定的mtDNA突变的传播多年来在没有强大的选择压力表明克隆持久性，但戏剧性的变化后，包括疾病转化和复发治疗后的瓶颈，收购拷贝数变异，染色质可及性和基因表达的变化。此外，我们将CLL亚克隆与不同的染色质状态联系起来，从而深入了解复发的非遗传来源。因此，mtDNA突变反映了疾病史，并提供了自然发生的遗传条形码，使癌症亚克隆动力学的患者特异性研究成为可能。
While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure indicating clonal persistence, but dramatic changes following tight bottlenecks including disease transformation and relapse post-therapy, paralleled by acquisition of copy number variants, changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into non-genetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally-occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics.