Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia

Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer . Chronic lymphocytic leukaemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution after therapy . The CLL epigenome is also...

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Published in:Nature (London) 2019-05, Vol.569 (7757), p.576-580
Main Authors: Gaiti, Federico, Chaligne, Ronan, Gu, Hongcang, Brand, Ryan M, Kothen-Hill, Steven, Schulman, Rafael C, Grigorev, Kirill, Risso, Davide, Kim, Kyu-Tae, Pastore, Alessandro, Huang, Kevin Y, Alonso, Alicia, Sheridan, Caroline, Omans, Nathaniel D, Biederstedt, Evan, Clement, Kendell, Wang, Lili, Felsenfeld, Joshua A, Bhavsar, Erica B, Aryee, Martin J, Allan, John N, Furman, Richard, Gnirke, Andreas, Wu, Catherine J, Meissner, Alexander, Landau, Dan A
Format: Article
Language:English
Subjects:
B cells
Base Sequence
Binding sites
Bioinformatics
Biological Clocks
Biological evolution
Bisulfite
Cancer
Cell differentiation
Cell Lineage - genetics
Chronic lymphocytic leukemia
Deoxyribonucleic acid
Differentiation (biology)
DNA
DNA Methylation
DNA sequencing
Epigenesis, Genetic
Epigenetic inheritance
Epigenetics
Epigenome - genetics
Evolution
Evolution, Molecular
Gene expression
Gene Expression Regulation, Neoplastic
Genetic aspects
Genetic diversity
Genetic research
Genetic transformation
Genomes
Genomics
Genotyping
Health aspects
Heterogeneity
Humans
Immunoglobulins
Integration
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Lymph nodes
Lymphocytes B
Lymphocytosis
Methylation
Mitochondrial DNA
Mutation
Mutation Rate
Phylogenetics
Populations
Sequence Analysis, RNA
Single-Cell Analysis
Stochasticity
Sulfites
Therapy
Transcription
Transcription (Genetics)
Transcription factors
Transcription, Genetic
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Summary:Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer . Chronic lymphocytic leukaemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution after therapy . The CLL epigenome is also an important disease-defining feature , and growing populations of cells in CLL diversify by stochastic changes in DNA methylation known as epimutations . However, previous studies using bulk sequencing methods to analyse the patterns of DNA methylation were unable to determine whether epimutations affect CLL populations homogeneously. Here, to measure the epimutation rate at single-cell resolution, we applied multiplexed single-cell reduced-representation bisulfite sequencing to B cells from healthy donors and patients with CLL. We observed that the common clonal origin of CLL results in a consistently increased epimutation rate, with low variability in the cell-to-cell epimutation rate. By contrast, variable epimutation rates across healthy B cells reflect diverse evolutionary ages across the trajectory of B cell differentiation, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed us to reconstruct lineages at high-resolution with single-cell data, and to apply this directly to patient samples. The CLL lineage tree shape revealed earlier branching and longer branch lengths than in normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. Integration of single-cell bisulfite sequencing analysis with single-cell transcriptomes and genotyping confirmed that genetic subclones mapped to distinct clades, as inferred solely on the basis of epimutation information. Finally, to examine potential lineage biases during therapy, we profiled serial samples during ibrutinib-associated lymphocytosis, and identified clades of cells that were preferentially expelled from the lymph node after treatment, marked by distinct transcriptional profiles. The single-cell integration of genetic, epigenetic and transcriptional information thus charts the lineage history of CLL and its evolution with therapy.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-019-1198-z