Citations 1
Genomic Architecture of IRF4 Rearrangements in Children and Adult Large B-cell Lymphomas
Colmenero, Ariadna , Frauenfeld, Leonie , Mato, Sara , Salmerón‐Villalobos, Julia , Arredondo-Prats, Vicente , Ramis-Zaldivar, Joan E. , Montaner, Anna, Anta, Natalia Castrejón de , González‐Farré, Blanca , Garcia, Noelia, Andión, Maitane, Azorín, Daniel, Celis, Verónica , Rodríguez-Pinilla, Socorro Maria, Santos, Carlos Aliste, Hsi, Eric, Gheorghe, Gabriela, Schafernak, Kristian T. , Shestakova, A M, Gutierrez, Francisco Llamas, Hebeda, Konnie M. , Bhavsar, Tapan Mahendra, López-Guillermo, A, Ramis-Zaldivar, Joan Enric , Castrejon-de-Anta, Natalia , Verdú-Amorós, Jaime , Andrés, Mara , Andión, Maitane , Celis, Verónica , Santos, Carlos Aliste , Hsi, Eric D , Mariani, Rachel , Schafernak, Kristian , Menon, Madhu P , Hebeda, Konnie , López-Guillermo, Armando , Jaffe, Elaine S , Quintanilla-Martinez, Leticia , Campo, Elías , Nadeu, Ferran , Salaverria, Itziar , Verdú‐Amorós, Jaime , Rodríguez-Pinilla, Socorro Marıá , Hsi, Eric D. , Shestakova, Anna , Bhavsar, Tapan M., López‐Guillermo, Armando , Jaffe, Elaine S. , Quintanilla‐Martínez, Leticia , Campo, Elı́as , Nadeu, Ferran , Balagué, Olga , Salaverría, Itziar
Blood Advances | July 17, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
10.1182/bloodadvances.2026020477
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.