Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes.

Aliki Xochelli, Panagiotis Baliakas, Ioannis Kavakiotis, Andreas Agathangelidis, Lesley-Ann Sutton, Eva Minga, Stavroula Ntoufa, Eugen Tausch, Xiao-Jie Yan, Tait Shanafelt, Karla Plevova, Myriam Boudjogra, Davide Rossi, Zadie Davis, Alba Navarro, Yorick Sandberg, Fie Juhl Vojdeman, Lydia Scarfo, Niki Stavroyianni, Andrey Sudarikov, Silvio Veronese, Tatiana Tzenou, Teodora Karan-Djurasevic, Mark Catherwood, Dirk Kienle, Maria Chatzouli, Monica Facco, Jasmin Bahlo, Christiane Pott, Lone Bredo Pedersen, Larry Mansouri, Karin E Smedby, Charles C Chu, Véronique Giudicelli, Marie-Paule Lefranc, Panagiotis Panagiotidis, Gunnar Juliusson, Achilles Anagnostopoulos, Ioannis Vlahavas, Darko Antic, Livio Trentin, Marco Montillo, Carsten Niemann, Hartmut Döhner, Anton W Langerak, Sarka Pospisilova, Michael Hallek, Elias Campo, Nicholas Chiorazzi, Nikos Maglaveras, David Oscier, Gianluca Gaidano, Diane F Jelinek, Stephan Stilgenbauer, Ioanna Chouvarda, Nikos Darzentas, Chrysoula Belessi, Frederic Davi, Anastasia Hadzidimitriou, Richard Rosenquist, Paolo Ghia, Kostas Stamatopoulos

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2018;23(17):5292-5301

PMID: 28536306

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Abstract

We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34-expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly ( < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. .

Address: Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Department of informatics, Aristotle University of Thessaloniki, Thessaloniki, Greece.; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.; Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.; Department of Internal Medicine III, Ulm University, Ulm, Germany.; Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York.; Department of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.; Central European Institute of Technology, Masaryk University, Brno, Czech Republic.; Department of Hematology, Hopital Pitie-Salpetriere and University Pierre et Marie Curie, Paris, France.; Division of Haematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.; Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom.; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.; Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.; Department of Hematology, Rigshospitalet, Copenhagen, Denmark.; Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.; National Research Center for Hematology, Moscow, Russia.; Molecular Pathology Unit and Haematology Department, Niguarda Cancer Center, Niguarda Ca' Granda Hospital, Milan, Italy.; First Department of Propaedeutic Medicine, University of Athens, Athens, Greece.; Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.; Department of Haemato-Oncology, Belfast City Hospital, Belfast, United Kingdom.; Hematology Department, Nikea General Hospital, Piraeus, Greece.; Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padova, Italy.; Department I of Internal Medicine and Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.; Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.; Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.; IMGT®, the international ImMunoGeneTics information system®, Université de Montpellier, LIGM, Institut de Génétique Humaine IGH, UPR CNRS 1142, Montpellier, France.; Lund University and Hospital Department of Hematology, Lund Stem Cell Center, Lund, Sweden.; Clinic for Hematology, Clinical Center, Belgrade, Serbia.; Medical faculty, University of Belgrade, Belgrade, Serbia.; Laboratory of Medical Informatics, Aristotle University of Thessaloniki, Thessaloniki, Greece.; Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States.; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece. [email protected].; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy.; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.

DOI: 10.1158/1078-0432.CCR-16-3100

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MeSH Terms: ADP-ribosyl Cyclase 1, Amino Acid Sequence, Female, Gene Expression Regulation, Neoplastic, Humans, Immunogenetics, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Somatic Hypermutation, Immunoglobulin