Genomic Architecture of IRF4 Rearrangements in Children and Adult Large B-cell Lymphomas

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) predominantly affects children and young adults (CAYA) and presents as localized disease with excellent prognosis. Although most tumors harbor IRF4 rearrangements (IRF4-R), the existence of cryptic rearrangements has been suggested. Whether IRF4-R LBCL in adults represents the same biological entity remains unclear. To address this question, 35 CAYA patients diagnosed with LBCL-IRF4 and 7 adult (>40-year-old) LBCL with IRF4-R were investigated by an integrative molecular approach. Targeted sequencing structural variant analysis (SV-NGS) confirmed the IRF4-R in 84% of investigated cases. In CAYA, an enrichment (55% vs 29% in adults) of translocations involving IGH, with a breakpoint cluster 3' to IRF4 (EXOC2) was observed, including a cryptic insertion of IGHM-IGHJ5 into IRF4 locus. Novel translocations, IRF4::MIR142 in two CAYA (7%) and IRF4::BATF in one adult, were discovered. Whole-exome sequencing analysis identified unreported mutations in LBCL-IRF4 as YY1 and ZC3H12A (11% each). The high incidence of mutations affecting the B-cell receptor/NF-KB pathways in LBCL-IRF4 was confirmed in cases with diffuse component only. None of the CAYA tumors were classified by LymphGen tool. Adult IRF4-R LBCL showed higher levels of genetic complexity and a distinct mutational profile with mutations on KMT2D and DTX1 (43% each), and MYD88-L265P (29%), and were predicted as EZB or MCD (29% each). These differential genetic features were in line with different clinical presentations (extranodal involvement and advanced stage). In conclusion, IRF4-R architecture and mutational profile differ according to age, supporting that not all cases should be classified as LBCL-IRF4.

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Journal
Blood Advances
Published
2026-07-16
DOI
https://doi.org/10.1182/bloodadvances.2026020477
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
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article

Genomic Architecture of IRF4 Rearrangements in Children and Adult Large B-cell Lymphomas

Verónica Celis, Joan E. Ramis-Zaldivar, Ariadna Colmenero, Jaime Verdú‐Amorós et al.
Blood Advances
Lymphoma Diagnosis and Treatment
article

Genomic Architecture of IRF4 Rearrangements in Children and Adult Large B-cell Lymphomas

Verónica Celis, Joan E. Ramis-Zaldivar, Ariadna Colmenero, Jaime Verdú‐Amorós, A M Shestakova, Leonie Frauenfeld, Olga Balagué, Konnie M. Hebeda, Sara Mato, Elı́as Campo, Leticia Quintanilla-Martı́nez, Julia Salmerón‐Villalobos, Kristian T. Schafernak, Blanca González‐Farré, Noelia Garcia, Anna Montaner, Mara Andrés, R Mariani, Ferran Nadeu, Madhu P. Menon, Itziar Salaverría, Maitane Andión, Natalia Castrejón de Anta, Elaine S. Jaffe, A López-Guillermo, Francisco Llamas Gutierrez, Carlos Aliste Santos, Daniel Azorín, Vicente Arredondo-Prats, Eric Hsi, Gabriela Gheorghe, Socorro Maria Rodríguez-Pinilla, Tapan Mahendra Bhavsar
article en

Abstract

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) predominantly affects children and young adults (CAYA) and presents as localized disease with excellent prognosis. Although most tumors harbor IRF4 rearrangements (IRF4-R), the existence of cryptic rearrangements has been suggested. Whether IRF4-R LBCL in adults represents the same biological entity remains unclear. To address this question, 35 CAYA patients diagnosed with LBCL-IRF4 and 7 adult (>40-year-old) LBCL with IRF4-R were investigated by an integrative molecular approach. Targeted sequencing structural variant analysis (SV-NGS) confirmed the IRF4-R in 84% of investigated cases. In CAYA, an enrichment (55% vs 29% in adults) of translocations involving IGH, with a breakpoint cluster 3' to IRF4 (EXOC2) was observed, including a cryptic insertion of IGHM-IGHJ5 into IRF4 locus. Novel translocations, IRF4::MIR142 in two CAYA (7%) and IRF4::BATF in one adult, were discovered. Whole-exome sequencing analysis identified unreported mutations in LBCL-IRF4 as YY1 and ZC3H12A (11% each). The high incidence of mutations affecting the B-cell receptor/NF-KB pathways in LBCL-IRF4 was confirmed in cases with diffuse component only. None of the CAYA tumors were classified by LymphGen tool. Adult IRF4-R LBCL showed higher levels of genetic complexity and a distinct mutational profile with mutations on KMT2D and DTX1 (43% each), and MYD88-L265P (29%), and were predicted as EZB or MCD (29% each). These differential genetic features were in line with different clinical presentations (extranodal involvement and advanced stage). In conclusion, IRF4-R architecture and mutational profile differ according to age, supporting that not all cases should be classified as LBCL-IRF4.

Blood Advances
National Institutes of Health (US), Hospital Sant Joan de Déu Barcelona (ES), St. Jude Children's Research Hospital (US), Mayo Clinic (US), Radboud University Nijmegen (NL), Universidade de Santiago de Compostela (ES), Radboud University Medical Center (NL), ARUP Laboratories (United States) (US), Hospital Clínico Universitario de Valencia (ES), Hospital Infantil Universitario Niño Jesús (ES), Hospital Clínic de Barcelona (ES), Leitat Technological Center (ES), Phoenix Children's Hospital (US), Hospital Universitario Fundación Jiménez Díaz (ES), Washington University Medical Center (US), National Cancer Institute (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University of Tübingen (DE)
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Lymphoma Diagnosis and Treatment
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