An Entity Evolving into a Community: Defining the Common Ancestor and Evolutionary Trajectory of Chronic Lymphocytic Leukemia Stereotyped Subset #4
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.
- 7.Li Z, Schettino EW, Padlan EA, Ikematsu H, Casali P. (2000) Structure-function analysis of a lupus anti-DNA autoantibody: central role of the heavy chain complementarity-determining region 3 Arg in binding of double- and single-stranded DNA. Eur. J. Immunol. 30:2015–26.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Hallek M, et al. (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 111:5446–56.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Dang QT, Phan TH. (2010) Determining Restricted Damerau-Levenshtein Edit-Distance of Two Languages by Extended Automata [Internet]. In: Computing and Communication Technologies, Research, Innovation, and Vision for the Future (RIVF), 2010 IEEE RIVF International Conference on; 2010 Nov 1–4; Hanoi. [cited 2015 Mar 31]. Available from: https://doi.org/ieeexplore.ieee.org/xpl/articleDetails.jsp?tp=&arnumber=5632914&queryText%3DDetermining+Restricted+Damerau-Levenshtein.
- 15.Gomez-Alonso C, Valls A. (2008) A Similarity Measure for Sequences of Categorical Data Based on the Ordering of Common Elements. In: Modeling Decisions for Artificial Intelligence: 5th International Conference, MDAI 2008, Sabadell, Spain, October 30–31, 2008, Proceedings. Torra V, Narukawa Y (eds.) Springer, Berlin, pp. 134–45.CrossRefGoogle Scholar
- 21.Erciyes K. (2013) Minimum spanning trees. In: Distributed graph algorithms for computer networks. Sammes AJ (ed.) Springer, pp. 69–82.Google Scholar
- 25.Catera R, et al. (2006) Polyreactive monoclonal antibodies synthesized by some B-CLL cells recognize specific antigens on viable and apoptotic T cells. Blood. 108:2813.Google Scholar
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.
The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)