title: An entity evolving into a community: defining the common ancestor and evolutionary trajectory of chronic lymphocytic leukemia stereotyped subset #4.
abstract: Patients with chronic lymphocytic leukemia (CLL) assigned to stereotyped subset #4 express highly homologous B-cell receptor immunoglobulin (BcR IG) sequences with intense intraclonal diversification (ID) in the context of ongoing somatic hypermutation (SHM). Their remarkable biological and clinical similarities strongly support derivation from a common ancestor. We here revisited ID in subset #4 CLL to reconstruct their evolutionary history as a community of related clones. To this end, using specialized bioinformatics tools we assessed both IGHV-IGHD-IGHJ rearrangements (n = 511) and IGKV-IGKJ rearrangements (n = 397) derived from eight subset #4 cases. Due to high sequence relatedness, a number of subclonal clusters from different cases lay very close to one another, forming a core from which clusters exhibiting greater variation stemmed. Minor subclones from individual cases were mutated to such an extent that they now resembled the sequences of another patient. Viewing the entire subset #4 data set as a single entity branching through diversification enabled inference of a common sequence representing the putative ancestral BcR IG expressed by their still elusive common progenitor. These results have implications for improved understanding of the ontogeny of CLL subset #4, as well as the design of studies concerning the antigenic specificity of the clonotypic BcR IGs.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Information Technologies Institute, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Papadopoulos
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hadzidimitriou
authors.affiliation: Information Technologies Institute, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Stavros
authors.initials: S
authors.lastname: Papadopoulos
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Efterpi
authors.initials: E
authors.lastname: Kostareli
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Information Technologies Institute, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tzovaras
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.|Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
mesh_terms: D000328:Adult; D000368:Aged; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged
chemical_list: D007136:Immunoglobulins