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| Home > Articles > Published articles > BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases |
(Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Barcelona Supercomputing Center) (Hospital Clínic i Provincial de Barcelona) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Hospital del Mar d'Investigacions Mèdiques) (Institut Hospital del Mar d'Investigacions Mèdiques) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut d'Investigació Biomèdica de Bellvitge) (Hospital Nostra Senyora de Meritxell. Escaldes-Engordany. Principat d'Andorra) (Hospital Clínic i Provincial de Barcelona) (Institut d'Investigació Biomèdica de Girona) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut d'Investigacions Biomèdiques August Pi i Sunyer)| Date: | 2024 |
| Abstract: | The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively. |
| Grants: | "la Caixa" Foundation LCF/PR/HR17/52150017 "la Caixa" Foundation LCF/PR/HR22/52420015 European Commission. Horizon 2020 810287 Agencia Estatal de Investigación PID2021-123054OB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021-SGR01172 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021-SGR-01293 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Published in: | Haematologica, Vol. 109 Núm. 2 (february 2024) , p. 493-508, ISSN 1592-8721 |
