NGS-based IG/TR gene rearrangement profiling in acute lymphoblastic leukemia: age dependence of immunogenetic maturation
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.
Authors
- Jacques J. M. van Dongen (ORCID: https://orcid.org/0000-0002-3650-7087)
- Monika Szczepanowski (ORCID: https://orcid.org/0000-0001-5482-8880)
- Julia Alten
- Martin Schrappe (ORCID: https://orcid.org/0000-0003-0034-5845)
- Michaela Kotrová (ORCID: https://orcid.org/0000-0001-5394-1072)
- Anna Laqua
- Claudia Dorothea Baldus (ORCID: https://orcid.org/0000-0002-0748-834X)
- Lorenz Bastian (ORCID: https://orcid.org/0000-0002-1487-9437)
- Stefan Schwartz (ORCID: https://orcid.org/0000-0001-8833-5793)
- Rolf Koehler
- Gunnar Cario (ORCID: https://orcid.org/0000-0001-8396-0127)
- Britta Kehden
- Sonja Bendig (ORCID: https://orcid.org/0009-0003-0644-9140)
- Guranda Chitadze (ORCID: https://orcid.org/0000-0001-9609-4643)
- Nicola Gökbuget
- Matthias Ritgen (ORCID: https://orcid.org/0000-0002-0957-3804)
- Željko Antić (ORCID: https://orcid.org/0000-0001-9398-2637)
- Saskia Kohlscheen
- Monika Brüggemann (ORCID: https://orcid.org/0000-0001-5514-5010)
- Nikos Darzentas
- Jan Christian Kässens (ORCID: https://orcid.org/0000-0001-7840-1160)
- Constantin Proske
- Anke K. Bergmann (ORCID: https://orcid.org/0000-0002-1367-2725)
- Wiebke Weßels
- Christiane Pott (ORCID: https://orcid.org/0009-0005-9260-8340)
Institutions
- Goethe University Frankfurt (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Hochschule für Angewandte Wissenschaften Kiel (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Medizinische Hochschule Hannover (DE)
- Humboldt-Universität zu Berlin (DE)
- German Cancer Society (DE)
- National Hemophilia Foundation (US)
- University Hospital Schleswig-Holstein (DE)
- Institute of Human Genetics (PL)
- Universitätsklinikum Würzburg (DE)
- University Hospital Frankfurt (DE)
- Clinical Research Center Kiel (DE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Blood
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1182/blood.2024027175
- Citations
- 4
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 7.51