Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia

Federico Gaiti, Ronan Chaligne, Hongcang Gu, Ryan M. Brand, Steven Kothen-Hill, Rafael C. Schulman, Kirill Grigorev, Davide Risso, Kyu-Tae Kim, Alessandro Pastore, Kevin Y. Huang, Alicia Alonso, Caroline Sheridan, Nathaniel D. Omans, Evan Biederstedt, Kendell Clement, Lili Wang, Joshua A. Felsenfeld, Erica B. Bhavsar, Martin J. Aryee, John N. Allan, Richard Furman, Andreas Gnirke, Catherine J. Wu, Alexander Meissner and Dan A. Landau ()
Additional contact information
Federico Gaiti: New York Genome Center
Ronan Chaligne: New York Genome Center
Hongcang Gu: Broad Institute of MIT and Harvard
Ryan M. Brand: New York Genome Center
Steven Kothen-Hill: New York Genome Center
Rafael C. Schulman: New York Genome Center
Kirill Grigorev: Weill Cornell Medicine
Davide Risso: Weill Cornell Medicine
Kyu-Tae Kim: New York Genome Center
Alessandro Pastore: Memorial Sloan Kettering Cancer Center
Kevin Y. Huang: New York Genome Center
Alicia Alonso: Weill Cornell Medicine
Caroline Sheridan: Weill Cornell Medicine
Nathaniel D. Omans: New York Genome Center
Evan Biederstedt: New York Genome Center
Kendell Clement: Broad Institute of MIT and Harvard
Lili Wang: City of Hope
Joshua A. Felsenfeld: Weill Cornell Medicine
Erica B. Bhavsar: Weill Cornell Medicine
Martin J. Aryee: Broad Institute of MIT and Harvard
John N. Allan: Weill Cornell Medicine
Richard Furman: Weill Cornell Medicine
Andreas Gnirke: Broad Institute of MIT and Harvard
Catherine J. Wu: Broad Institute of MIT and Harvard
Alexander Meissner: Broad Institute of MIT and Harvard
Dan A. Landau: New York Genome Center

Nature, 2019, vol. 569, issue 7757, 576-580

Abstract: Abstract Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer1. Chronic lymphocytic leukaemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution after therapy2,3. The CLL epigenome is also an important disease-defining feature4,5, and growing populations of cells in CLL diversify by stochastic changes in DNA methylation known as epimutations6. 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.

Date: 2019
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DOI: 10.1038/s41586-019-1198-z

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