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Longitudinal single-cell dynamics of chromatin accessibility and mitochondrial mutations in chronic lymphocytic leukemia mirror disease history

Item Type:Article
Title:Longitudinal single-cell dynamics of chromatin accessibility and mitochondrial mutations in chronic lymphocytic leukemia mirror disease history
Creators Name:Penter, L. and Gohil, S.H. and Lareau, C. and Ludwig, L.S. and Parry, E.M. and Huang, T. and Li, S. and Zhang, W. and Livitz, D. and Leshchiner, I. and Parida, L. and Getz, G. and Rassenti, L.Z. and Kipps, T.J. and Brown, J.R. and Davids, M.S. and Neuberg, D.S. and Livak, K.J. and Sankaran, V.G. and Wu, C.J.
Abstract: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.
Keywords:Chronic Lymphocytic Leukemia, Mitochondrial DNA Mutations, Clonal Evolution, Single Cell ATAC Sequencing, Transcriptional State
Source:Cancer Discovery
ISSN:2159-8274
Publisher:American Association for Cancer Research
Date:10 June 2021
Official Publication:https://doi.org/10.1158/2159-8290.CD-21-0276
PubMed:View item in PubMed

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