title: Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse.
abstract: The strongest predictor of relapse in B-cell acute lymphoblastic leukemia (B-ALL) is the level of persistence of tumor cells after initial therapy. The high mutation rate of the B-cell receptor (BCR) locus allows high-resolution tracking of the architecture, evolution and clonal dynamics of B-ALL. Using longitudinal BCR repertoire sequencing, we find that the BCR undergoes an unexpectedly high level of clonal diversification in B-ALL cells through both somatic hypermutation and secondary rearrangements, which can be used for tracking the subclonal composition of the disease and detect minimal residual disease with unprecedented sensitivity. We go on to investigate clonal dynamics of B-ALL using BCR phylogenetic analyses of paired diagnosis-relapse samples and find that large numbers of small leukemic subclones present at diagnosis re-emerge at relapse alongside a dominant clone. Our findings suggest that in all informative relapsed patients, the survival of large numbers of clonogenic cells beyond initial chemotherapy is a surrogate for inherent partial chemoresistance or inadequate therapy, providing an increased opportunity for subsequent emergence of fully resistant clones. These results frame early cytoreduction as an important determinant of long-term outcome.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: R J M
authors.initials: RJ
authors.lastname: Bashford-Rogers
authors.affiliation: The Center for the Study of Hematological Malignancies, Nicosia, Cyprus.
authors.forename: K A
authors.initials: KA
authors.lastname: Nicolaou
authors.affiliation: Department of Haematology, Great Ormond Street Hospital for Children, London, UK.|Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Bartram
authors.affiliation: Department of Haematology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Goulden
authors.affiliation: Pediatric Oncology/Hematology Clinic, Nicosia, Cyprus.
authors.forename: L
authors.initials: L
authors.lastname: Loizou
authors.affiliation: The Center for the Study of Hematological Malignancies, Nicosia, Cyprus.
authors.forename: L
authors.initials: L
authors.lastname: Koumas
authors.affiliation: The Center for the Study of Hematological Malignancies, Nicosia, Cyprus.
authors.forename: J
authors.initials: J
authors.lastname: Chi
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Hubank
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|Division of Infection and Immunity, Research Department of Infection, University College London, London, UK.
authors.forename: P
authors.identifier: 0000-0003-3166-4734
authors.initials: P
authors.lastname: Kellam
authors.affiliation: The Center for the Study of Hematological Malignancies, Nicosia, Cyprus.
authors.forename: P A
authors.initials: PA
authors.lastname: Costeas
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|The Center for the Study of Hematological Malignancies, Nicosia, Cyprus.|Cambridge Blood and Stem Cell Biobank and Cancer Molecular Diagnosis Laboratory, Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: G S
authors.initials: GS
authors.lastname: Vassiliou
mesh_terms: D002470:Cell Survival; D002999:Clone Cells / Q000473:pathology; D006801:Humans; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011379:Prognosis; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D012008:Recurrence; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics
chemical_list: D011947:Receptors, Antigen, B-Cell