NGS-based IG/TR gene rearrangement profiling in acute lymphoblastic leukemia: age dependence of immunogenetic maturation
Abstract
Abstract We comprehensively profiled the landscape of immunoglobulin (IG) and T-cell receptor (TR) rearrangements at diagnosis in 1212 patients with acute lymphoblastic leukemia (ALL; 573 children and 639 adults) diagnosed in Germany between 2017 and 2022. Our study revealed a significant age-related decrease in immunogenetic maturation, where IG κ rearrangements in B-ALL and complete TR β/δ rearrangements in T-ALL, hallmarks of maturity, were more frequent in pediatric patients compared to adults (B-ALL: 68.7% vs 39.0%, P < 2.2e-16; T-ALL: 85.7% vs 67.3%, P = 6.7e-03). Compared to adults, children had a higher average number of IG/TR markers per patient (6 vs 4; P = 2.5e-38) and markedly fewer lacked these markers (0.5% compared to 6.7%). IG heavy chain clonal evolution was most pronounced among pro-B-ALL cases (60.9%), with the V-to-DJ mechanism driving pro-B evolution (78.6%), whereas V-replacement dominated other immunophenotypes. Furthermore, expanded accompanying T-cell clones of unknown significance in B-ALL increased with age. This next-generation sequencing-based study offers an unprecedented characterization of IG/TR rearrangement patterns across ALL subtypes and age groups. It highlights the higher immunogenetic maturity in children, which may be explained by the infection-driven abnormal activity of the IG/TR recombination machinery in pediatric ALL.
Article Details
Authors (25)
Michaela Kotrova
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Constantin Proske
1Department of Internal Medicine II, University Medical Center Schleswig-Holstein, Kiel, Germany
Nikos Darzentas
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Anna Laqua
1University Hospital Schleswig-Holstein, Medical Department II, Hematology/Oncology, Kiel, Germany
Britta Kehden
Medical Department II, Hematology/Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
Jan Kässens
1Department of Internal Medicine II, University Medical Center Schleswig-Holstein, Kiel, Germany
Sonja Bendig
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Saskia Kohlscheen
7University Medical Center Schleswig-Holstein, Campus Kiel, Department of Internal Medicine II, University of Schleswig-Holstein, Kiel, Kiel, Germany
Monika Szczepanowski
1University Hospital Schleswig-Holstein, Medical Department II, Hematology/Oncology, Kiel, Germany
Wiebke Wessels
Željko Antić
University Hospital Würzburg, Würzburg, Germany
Christiane Pott
6University Hospital Schleswig-Holstein, Department of Internal Medicine II, Kiel, Germany
Matthias Ritgen
Universitaetsklinikum Schleswig-Holstein, Medizinische Klinik II, Kiel, Germany
Jacques J. M. van Dongen
5European Scientific Foundation for Laboratory Hemato-Oncology, Zutphen, The Netherlands
Nicola Gökbuget
26Department of Medicine II, Hematology/Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
Guranda Chitadze
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Anke Bergmann
6University Hospital Würzburg, Würzburg, Germany
Lorenz Bastian
Claudia D. Baldus
Gunnar Cario
University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
Martin Schrappe
Stefan Schwartz
23Department of Hematology, Oncology and Cancer Immunology (Campus Benjamin Franklin), Charité– Universitätsmedizin Berlin, corporate member of Freie Universität and Humboldt-Universität zu Berlin, Berlin, Germany
Julia Alten
Dept. of Pediatrics, UKSH, Kiel, Germany
Rolf Köhler
10University Medical Center Heidelberg, Institute of Human Genetics, Heidelberg, Germany
Monika Brüggemann
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany