title: Evolution of multiple cell clones over a 29-year period of a CLL patient.
abstract: Chronic lymphocytic leukaemia (CLL) is a frequent B-cell malignancy, characterized by recurrent somatic chromosome alterations and a low level of point mutations. Here we present single-nucleotide polymorphism microarray analyses of a single CLL patient over 29 years of observation and treatment, and transcriptome and whole-genome sequencing at selected time points. We identify chromosome alterations 13q14-, 6q- and 12q+ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and chromosome 10 copy-neutral loss of heterogeneity that marks a major population dominant at death. Serial single-cell RNA sequencing reveals an expression pattern with high FOS, JUN and KLF4 at disease acceleration, which resolves following therapy, but reoccurs following relapse and death. Transcriptome evolution indicates complex changes in expression occur over time. In conclusion, CLL can evolve gradually during indolent phases, and undergo rapid changes following therapy.
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China.|School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Zhikun
authors.identifier: http://orcid.org/0000-0001-5161-7818
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Goldin
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Liu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wu
authors.affiliation: Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Bethesda, Maryland 20892, USA.
authors.forename: Weiyin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Bethesda, Maryland 20892, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Lou
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|BGI-Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China.
authors.forename: Qichao
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Biomatrix, Bethesda, Maryland 20849, USA.
authors.forename: Shirley X
authors.initials: SX
authors.lastname: Tsang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Jiang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Li
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: MaryLou
authors.initials: M
authors.lastname: McMaster
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Lin
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Liqin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland 20993, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Marti
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|Department of Biology, University of Copenhagen, Copenhagen 1599, Denmark.
authors.forename: Guibo
authors.initials: G
authors.lastname: Li
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|Department of Biology, University of Copenhagen, Copenhagen 1599, Denmark.
authors.forename: Kui
authors.initials: K
authors.lastname: Wu
authors.affiliation: Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Bethesda, Maryland 20892, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|James D. Watson Institute of Genome Sciences, Hangzhou 310058, China.
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|Department of Biology, University of Copenhagen, Copenhagen 1599, Denmark.
authors.forename: Yong
authors.identifier: http://orcid.org/0000-0002-0420-0726
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0003-2234-0631
authors.initials: M
authors.lastname: Dean
mesh_terms: D000368:Aged; D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D060965:Clonal Evolution / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D007107:Immune System / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000235:genetics
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D012313:RNA; D004247:DNA