Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults

Author:

Salaverria Itziar1,Philipp Claudia2,Oschlies Ilske3,Kohler Christian W.4,Kreuz Markus5,Szczepanowski Monika3,Burkhardt Birgit6,Trautmann Heiko7,Gesk Stefan1,Andrusiewicz Miroslaw18,Berger Hilmar5,Fey Miriam1,Harder Lana1,Hasenclever Dirk5,Hummel Michael9,Loeffler Markus5,Mahn Friederike1,Martin-Guerrero Idoia1,Pellissery Shoji1,Pott Christiane7,Pfreundschuh Michael10,Reiter Alfred6,Richter Julia1,Rosolowski Maciej5,Schwaenen Carsten11,Stein Harald9,Trümper Lorenz12,Wessendorf Swen11,Spang Rainer4,Küppers Ralf2,Klapper Wolfram3,Siebert Reiner1, , ,

Affiliation:

1. Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany;

2. Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, Essen, Germany;

3. Department of Pathology, Hematopathology Section and Lymph Node, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany;

4. Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;

5. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany;

6. Department of Pediatric Hematology and Oncology, Justus-Liebig University, Giessen, Germany;

7. Second Medical Department, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany;

8. Department of Cell Biology, University of Medical Sciences, Poznan, Poland;

9. Institute of Pathology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany;

10. Department of Internal Medicine I, University of Saarland, Homburg, Germany;

11. Internal Medicine III, University Hospital of Ulm, Ulm, Germany; and

12. Department of Hematology and Oncology, Georg-August University of Göttingen, Göttingen, Germany

Abstract

Abstract The prognosis of germinal center–derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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