title: Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding.
abstract: Genetic and phenotypic heterogeneity of human leukemia is thought to drive leukemia progression through a Darwinian process of selection and evolution of increasingly malignant clones. However, the lack of markers that uniquely identify individual leukemia clones precludes high-resolution tracing of their clonal dynamics. Here, we use cellular barcoding to analyze the clonal behavior of patient-derived leukemia-propagating cells (LPCs) in murine xenografts. Using a leukemic cell line and diagnostic bone marrow cells from 6 patients with B-progenitor cell acute lymphoblastic leukemia, we demonstrate that patient-derived xenografts were highly polyclonal, consisting of tens to hundreds of LPC clones. The number of clones was stable within xenografts but strongly reduced upon serial transplantation. In contrast to primary recipients, in which clonal composition was highly diverse, clonal composition in serial xenografts was highly similar between recipients of the same donor and reflected donor clonality, supporting a deterministic, clone-size-based model for clonal selection. Quantitative analysis of clonal abundance in several anatomic sites identified 2 types of anatomic asymmetry. First, clones were asymmetrically distributed between different bones. Second, clonal composition in the skeleton significantly differed from extramedullary sites, showing similar numbers but different clone sizes. Altogether, this study shows that cellular barcoding and xenotransplantation providea useful model to study the behavior of patient-derived LPC clones, which provides insights relevant for experimental studies on cancer stem cells and for clinical protocols for the diagnosis and treatment of leukemia.
authors.affiliation: Department of Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands.|Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; and.
authors.forename: Mirjam E
authors.initials: ME
authors.lastname: Belderbos
authors.affiliation: Department of Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Taco
authors.initials: T
authors.lastname: Koster
authors.affiliation: Department of Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Bertien
authors.initials: B
authors.lastname: Ausema
authors.affiliation: Department of Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jacobs
authors.affiliation: Department of Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Sharlaine
authors.initials: S
authors.lastname: Sowdagar
authors.affiliation: Department of Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Zwart
authors.affiliation: Department of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Eveline
authors.initials: E
authors.lastname: de Bont
authors.affiliation: Department of Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
authors.affiliation: Department of Stem Cell Biology and Ageing, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Bystrykh
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018448:Models, Immunological; D009368:Neoplasm Transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology