HIGHER-ORDER IMMUNOGLOBULIN SEQUENCE RELATIONS FOR MAJOR SUBSETS OF CHRONIC LYMPHOCYTIC LEUKEMIA: UNIQUENESS VERSUS EQUIVALENCE
Author(s): ,
Andreas Agathangelidis
Affiliations:
Division of Experimental Oncology and Department of Onco-Hematology,San Raffaele Scientific Institute and Università Vita-Salute San Raffaele,Milan,Italy
,
Vojtech Bystry
Affiliations:
Masaryk University,Central European Institute of Technology,Brno,Czech Republic
,
Anastasia Hadzidimitriou
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece
,
Lesley-Ann Sutton
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Eva Minga
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece
,
Dirk Kienle
Affiliations:
Department of Internal Medicine III,Ulm University,Ulm,Germany
,
Zadie Davis
Affiliations:
Department of Haematology,Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Xiao-Jie Yan
Affiliations:
Feinstein Institute for Medical Research,North Shore-Long Island Jewish Health System,Manhasset,United States
,
Tait Shanafelt
Affiliations:
Department of Hematology, Department of Medicine,Mayo Clinic,Rochester, Minnesota,United States
,
Myriam Boudjogra
Affiliations:
Hematology Department and University Pierre et Marie Curie,Hopital Pitie-Salpetriere,Paris,France
,
Karla Plevova
Affiliations:
Masaryk University,Central European Institute of Technology,Brno,Czech Republic;University Hospital Brno,Brno,Czech Republic
,
Maria Gounari
Affiliations:
Division of Experimental Oncology and Department of Onco-Hematology,San Raffaele Scientific Institute and Università Vita-Salute San Raffaele,Milan,Italy
,
Aliki Xochelli
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece
,
Alba Navarro
Affiliations:
Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Maria Chatzouli
Affiliations:
Hematology Department,Nikea General Hospital,Piraeus,Greece
,
Lone Bredo Pedersen
Affiliations:
Department of Hematology,Rigshospitalet,Copenhagen,Denmark
,
Panagiotis Baliakas
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Lydia Scarfò
Affiliations:
Division of Experimental Oncology and Department of Onco-Hematology,San Raffaele Scientific Institute and Università Vita-Salute San Raffaele,Milan,Italy
,
Davide Rossi
Affiliations:
Hematology Department,Amedeo Avogadro University of Eastern Piedmont,Novara,Italy
,
Silvio Veronese
Affiliations:
Molecular Pathology Unit and Haematology Department,Niguarda Cancer Center, Niguarda Ca’ Granda Hospital,Milan,Italy
,
Monica Facco
Affiliations:
Department of Medicine, Hematology and Clinical Immunology Branch,Padua University School of Medicine,Padova,Italy
,
Vasilis Bikos
Affiliations:
Masaryk University,Central European Institute of Technology,Brno,Czech Republic
,
Teodora Karan-Djurasevic
Affiliations:
Institute of Molecular Genetics and Genetic Engineering,University of Belgrade,Belgrade,Serbia
,
Sonja Pavlovic
Affiliations:
University of Kragujevac,Kragujevac,Serbia
,
Larry Mansouri
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Claire Poiron
Affiliations:
IMGT®, the international ImMunoGeneTics information system®,Université d Montpellier, LIGM, Institut de Génétique Humaine IGH,Montpellier,France
,
Charles C Chu
Affiliations:
Feinstein Institute for Medical Research,North Shore-Long Island Jewish Health System,Manhasset,United States
,
Evangelia Stalika
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece
,
Véronique Giudicelli
Affiliations:
IMGT®, the international ImMunoGeneTics information system®,Université d Montpellier, LIGM, Institut de Génétique Humaine IGH,Montpellier,France
,
Panagiotis Panagiotidis
Affiliations:
First Department of Propaedeutic Medicine,University of Athens,Athens,Greece
,
Andrey Sudarikov
Affiliations:
Department of Molecular Hematology,National Hematology Research Center,Moscow,Russian Federation
,
Achilles Anagnostopoulos
Affiliations:
Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece
,
Livio Trentin
Affiliations:
Department of Medicine, Hematology and Clinical Immunology Branch,Padua University School of Medicine,Padova,Italy
,
Mark Catherwood
Affiliations:
Department of Hemato-Oncology,Belfast City Hospital,Belfast,United Kingdom
,
Marco Montillo
Affiliations:
Molecular Pathology Unit and Haematology Department,Niguarda Cancer Center, Niguarda Ca’ Granda Hospital,Milan,Italy
,
Gianluca Gaidano
Affiliations:
Hematology Department,Amedeo Avogadro University of Eastern Piedmont,Novara,Italy
,
Elias Campo
Affiliations:
Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona,Spain
,
Christian H Geisler
Affiliations:
Department of Hematology,Rigshospitalet,Copenhagen,Denmark
,
Anton W Langerak
Affiliations:
Department of Immunology, University Medical Center Rotterdam,Erasmus MC,Rotterdam,Netherlands
,
Sarka Pospisilova
Affiliations:
Masaryk University,Central European Institute of Technology,Brno,Czech Republic;University Hospital Brno,Brno,Czech Republic
,
Marie-Paule Lefranc
Affiliations:
IMGT®, the international ImMunoGeneTics information system®,Université d Montpellier, LIGM, Institut de Génétique Humaine IGH,Montpellier,France
,
Nicholas Chiorazzi
Affiliations:
Feinstein Institute for Medical Research,North Shore-Long Island Jewish Health System,Manhasset,United States
,
David Oscier
Affiliations:
Department of Haematology,Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Diane F Jelinek
Affiliations:
Department of Immunology,Mayo Clinic,Rochester, Minnesota,United States
,
Stephan Stilgenbauer
Affiliations:
Department of Internal Medicine III,Ulm University,Ulm,Germany
,
Chrysoula Belessi
Affiliations:
Hematology Department,Nikea General Hospital,Piraeus,Greece
,
Frederic Davi
Affiliations:
Hematology Department and University Pierre et Marie Curie,Hopital Pitie-Salpetriere,Paris,France
,
Richard Rosenquist
Affiliations:
Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
,
Paolo Ghia
Affiliations:
Division of Experimental Oncology and Department of Onco-Hematology,San Raffaele Scientific Institute and Università Vita-Salute San Raffaele,Milan,Italy
,
Nikos Darzentas
Affiliations:
Masaryk University,Central European Institute of Technology,Brno,Czech Republic
Kostas Stamatopoulos
Affiliations:
Institute of Applied Biosciences,CERTH,Thessaloniki,Greece;Hematology Department and HCT Unit,G. Papanicolaou Hospital,Thessaloniki,Greece;Department of Immunology, Genetics and Pathology, Science for Life Laboratory,Uppsala University,Uppsala,Sweden
EHA Library. Agathangelidis A. Jun 12, 2015; 100454; P199 Disclosure(s): San Raffaele Scientific Institute
Department of Experimental Onclology
Dr. Andreas Agathangelidis
Dr. Andreas Agathangelidis
Contributions
Abstract
Abstract: P199

Type: Poster Presentation

Presentation during EHA20: From 12.06.2015 17:15 to 12.06.2015 18:45

Location: Poster area (Hall C)

Background
Studies of the B cell receptor immunoglobulin (BcR IG) in chronic lymphocytic leukemia (CLL) revealed that ~30% of cases can be assigned to stereotyped subsets. In our previous publication of 7,596 CLL BcR IG gene sequences, we focused on 19 major subsets, collectively accounting for 12% of the cohort. This process was based on the implementation of stringent criteria focusing on high sequence relatedness. However, we have been aware of BcR IG sequences similar to those in or even between major subsets, yet set apart due to not fulfilling the adopted criteria.

Aims
We systematically searched for previously obscured sequence relatives of major BcR IG stereotypes with the aim of obtaining a wider, better connected, and thus more insightful view into IG repertoire restriction in CLL.

Methods
Sequence relatives of major subsets were sought for through applying a series of criteria in reference to each respective subset: (i) usage of the same IGH genes, (ii) VH CDR3 length difference ranging from -2 to +2 amino acids (aa); and, (iii) expression of the same VH CDR3 sequence motif. A total of 20331 productive IGHV-IGHD-IGHJ gene rearrangements from a multi-institutional series of CLL patients were evaluated, with assignment to major subsets performed with purpose-built bioinformatics methods. 

Results
Overall, 2450/20331 (12.1%) CLL sequences formed the 19 major subsets, each containing 44 to 548 sequences. The relative frequency of each major subset was highly similar between the present and the previous analysis, justifying their consideration as major. The quest for sequence relatives to major subsets was performed individually for each subset. For major subsets with mutated IGHV genes (M-CLL), generally, very few non-subset sequences showed adequate VH CDR3 similarity, and even these utilized different IGHV genes, thus not satisfying our search criteria. Amongst subsets with unmutated IGHV genes (U-CLL), a striking case of relatedness was observed between major subsets #1 (501 cases) and #99 (70 cases), characterized by the usage of the same IGH genes and the presence of a shared QWL motif at the same positions within VH CDR3. Their single important difference concerned VH CDR3 length (subset #1: 13 aa, subset #99: 14 aa). For the remaining major U-CLL subsets, certain subsets remained “unique”, contrasting others for which we identified closely related sequences we now deem as “satellite” subsets. In particular, in the case of subset #8 (IGHV4-39) we identified two “satellite” subsets that consisted of 35 and 10 cases and displayed relative sizes of 37.6% and 10.8% (compared to subset #8), respectively. Even more pronounced was the case of subset #31 (IGHV3-48), with its “satellite” comprising of 51 sequences and a relative size of 86.4% compared to subset #31, thus almost equal to its established relative. 

Summary
Major M-CLL stereotyped subsets remained isolated, with unique sequence characteristics. In contrast, a clear trend was evident for many major U-CLL subsets in having “satellites”, potentially functionally equivalent, and often large in size. These findings could be attributed to the intrinsic differences between M-CLL versus U-CLL subsets in terms of IG gene repertoire and VH CDR3 features. Considering that major stereotyped subsets may indeed represent distinct disease subgroups, our highlighting of higher-order sequence relations has implications for clinicobiological research aimed at dissecting the heterogeneity of CLL towards identifying distinct profiles that would assist in clinical decision making.

Keyword(s): CDR3, Chronic lymphocytic leukemia, Immunoglobulin gene

Session topic: CLL - Biology: Microenvironmental interactions

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