Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
Cancer Res. 2023 Mar 2;83(5):667-672. doi: 10.1158/0008-5472.CAN-22-0275.
Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin using sequencing (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy-number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant. This study thus demonstrates the feasibility and utility of multi-modal single-cell and natural barcoding approaches to characterize murine cancer models.
mtDNA mutations can serve as natural barcodes to enable lineage tracing in murine cancer models, which can be used to provide new insights into disease biology and to identify therapeutic vulnerabilities.
小鼠模型是功能基因组研究和新型治疗方法的临床前测试不可或缺的工具。 使用测序的转座酶可及染色质的单细胞分析 (mtscATAC-seq) 通过捕获染色质可及性、拷贝数变异 (CNV) 和线粒体 DNA (mtDNA) 突变，能够剖析细胞异质性和克隆动力学，但它在小鼠研究中的适用性仍未得到探索。 通过在新型慢性淋巴细胞白血病和里希特综合征小鼠模型中利用 mtscATAC-seq，我们报告了 mtDNA 突变的检测，特别是在高度增殖的小鼠细胞中，以及伴随二级移植后克隆进化的 CNV 和染色质状态变化。 因此，这项研究证明了多模态单细胞和自然条形码方法用于表征小鼠癌症模型的可行性和实用性。
mtDNA 突变可以作为谱系追踪的天然条形码，用于为疾病生物学提供新的见解，并确定治疗弱点。
