@article{10902/32671,
year = {2024},
url = {https://hdl.handle.net/10902/32671},
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.},
organization = {Funding: This study was supported by the “la Caixa" Foundation (CLLEvolution - LCF/PR/HR17/52150017 [HR17-00221LCF] and CLLSYSTEMS - LCF/PR/HR22/52420015 [HR22-00172] Health Research 2017 and 2022 Programs, to EC), the European Research Council (to EC and JIM-S) under the European Union’s Horizon 2020 research and innovation program (810287, BCLLatlas, to EC), Ministry of Science and Innovation (MCIN) /AEI/10.13039/501100011033/ and European Regional Development Fund “Una manera de hacer Europa” (PID2021-123054OB-I00 to EC) and the Generalitat de Catalunya Suport Grups de Recerca AGAUR (2021-SGR-01172 to EC and 2021-SGR-01293 to SB). HP-A is a recipient of a pre-doctoral fellowship from the Spanish Ministry of Science, Innovation and Universities (FPU19/03110). MD-F acknowledges the research support from the AECC Scientific Foundation. FN acknowledges research support from the American Association for Cancer Research (2021 AACRAmgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245), and Lady Tata Memorial Trust (International Award for Research in Leukemia 2021-2022, LADY_TATA_21_3223). EC is an Academia Researcher of the “Institució Catalana de Recerca i Estudis Avançats” (ICREA) of the Generalitat de Catalunya.
Acknowledgments: The authors thank the Hematopathology Collection registered at the Biobank of Hospital Clí nic - Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), the Biobank HUB-ICO-IDIBELL (PT17/0015/0024), integrated in the Spanish Biobank Network and funded by Instituto de Salud Carlos III (PT17/0015/0024), and Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncologia de Catalunya (XBTC), and the Molecular Cytogenetics Platform of IMIM, Hospital del Mar (Barcelona) for providing BAC clones. This work was partially developed at the Center Esther Koplowitz (CEK, Barcelona, Spain).},
publisher = {Ferrata Storti Foundation},
publisher = {Haematologica, 2024, 109, 2},
title = {BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases},
author = {Carbo-Meix, Anna and Guijarro, Francesca and Wang, Luojun and Grau, Marta and Royo, Romina and Frigola, Gerard and Playa-Albinyana, Heribert and Buhler, Marco M. and Clot, Guillem and Duran-Ferrer, Marti and Lu, Junyan and Granada, Isabel and Baptista, Maria-Joao and Navarro, Jose-Tomas and Espintet, Blanca and Puiggros, Anna and Tapia, Gustavo and Bandiera, Laura and Yáñez San Segundo, Lucrecia},
}