Molecular Medicine

, Volume 20, Issue 1, pp 720–728 | Cite as

An Entity Evolving into a Community: Defining the Common Ancestor and Evolutionary Trajectory of Chronic Lymphocytic Leukemia Stereotyped Subset #4

  • Lesley-Ann Sutton
  • Giorgos Papadopoulos
  • Anastasia Hadzidimitriou
  • Stavros Papadopoulos
  • Efterpi Kostareli
  • Richard Rosenquist
  • Dimitrios Tzovaras
  • Kostas Stamatopoulos
Research Article


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.



This work was supported in part by the Swedish Cancer Society, the Swedish Research Council, and the Lion’s Cancer Research Foundation, Uppsala; the ENosAI project (code 09SYN-13-880) cofunded by the EU and the Hellenic General Secretariat for Research and Technology; the KRIPIS action, funded by the Hellenic General Secretariat for Research and Technology and the European Regional Development Fund of the EU under the O.P. Competitiveness and Entrepreneurship, NSRF 2007–2013.

Supplementary material

10020_2014_2001720_MOESM1_ESM.pdf (2.7 mb)
Supplementary material, approximately 2.73 MB.


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Authors and Affiliations

  • Lesley-Ann Sutton
    • 1
  • Giorgos Papadopoulos
    • 2
  • Anastasia Hadzidimitriou
    • 1
    • 3
  • Stavros Papadopoulos
    • 2
  • Efterpi Kostareli
    • 4
  • Richard Rosenquist
    • 1
  • Dimitrios Tzovaras
    • 2
  • Kostas Stamatopoulos
    • 1
    • 3
    • 5
  1. 1.Department of Immunology, Genetics and Pathology, Science for Life LaboratoryUppsala UniversityUppsalaSweden
  2. 2.Information Technologies InstituteCenter for Research and Technology HellasThessalonikiGreece
  3. 3.Institute of Applied BiosciencesCenter for Research and Technology HellasThessalonikiGreece
  4. 4.Division of Epigenomics and Cancer Risk FactorsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  5. 5.Hematology Department and HCT UnitG. Papanicolaou HospitalThessalonikiGreece

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