title: Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia.
abstract: The ability to distinguish clonal B-cell populations based on the sequence of their rearranged immunoglobulin heavy chain (IgH) locus is an important tool for diagnosing B-cell neoplasms and monitoring treatment response. Leukemic precursor B cells may continue to undergo recombination of the IgH gene after malignant transformation; however, the magnitude of evolution at the IgH locus is currently unknown. We used next-generation sequencing to characterize the repertoire of IgH sequences in diagnostic samples of 51 children with B precursor acute lymphoblastic leukemia (B-ALL). We identified clonal IgH rearrangements in 43 of 51 (84%) cases and found that the number of evolved IgH sequences per patient ranged dramatically from 0 to 4024. We demonstrate that the evolved IgH sequences are not the result of amplification artifacts and are unique to leukemic precursor B cells. In addition, the evolution often follows an allelic exclusion pattern, where only 1 of 2 rearranged IgH loci exhibit ongoing recombination. Thus, precursor B-cell leukemias maintain evolution at the IgH locus at levels that were previously underappreciated. This finding sheds light on the mechanisms associated with leukemic clonal evolution and may fundamentally change approaches for monitoring minimal residual disease burden.
authors.affiliation: Division of Hematology-Oncology-Stem Cell Transplantation and Cancer Biology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. cgawad@stanford.edu
authors.forename: Charles
authors.initials: C
authors.lastname: Gawad
authors.forename: Francois
authors.initials: F
authors.lastname: Pepin
authors.forename: Victoria E H
authors.initials: VE
authors.lastname: Carlton
authors.forename: Mark
authors.initials: M
authors.lastname: Klinger
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Logan
authors.forename: David B
authors.initials: DB
authors.lastname: Miklos
authors.forename: Malek
authors.initials: M
authors.lastname: Faham
authors.forename: Gary
authors.initials: G
authors.lastname: Dahl
authors.forename: Norman
authors.initials: N
authors.lastname: Lacayo
mesh_terms: D000367:Age Factors; D000465:Algorithms; D001853:Bone Marrow / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D060965:Clonal Evolution / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D012008:Recurrence; D054928:Validation Studies as Topic