Authors
Ariadna Colmenero, Leonie Frauenfeld, Sara Mato, Julia Salmerón-Villalobos, Vicente Arredondo-Prats, Joan Enric Ramis-Zaldivar, Anna Montaner, Natalia Castrejon-de-Anta, Blanca Gonzalez-Farre, Noelia Garcia, Jaime Verdu-Amorós, Mara Andres, Maitane Andión, Daniel Azorín, Verónica Celis, Socorro Maria Rodríguez-Pinilla, Carlos Aliste Santos, Eric Hsi, Gabriela Gheorghe, Rachel Angelica Mariani, Kristian T Schafernak, Anna Shestakova, Madhu Menon, Francisco Llamas Gutierrez, Konnie M Hebeda, Tapan Mahendra Bhavsar, Armando López-Guillermo, Elaine S Jaffe, Leticia Quintanilla-Martinez, Elías Campo, Ferran Nadeu, Olga Balagué, Itziar Salaverria
Published in
Blood advances. Jul 16, 2026. Epub Jul 16, 2026.
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.
PMID:
42466980
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.
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