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BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases

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.

 Fuente: Haematologica, 2024, 109, 2

 Editorial: Ferrata Storti Foundation

 Año de publicación: 2024

 Nº de páginas: 16

 Tipo de publicación: Artículo de Revista

 ISSN: 0390-6078,1592-8721

 Proyecto español: /AEI/10.13039/501100011033/

 Url de la publicación: 10.3324/haematol.2023.283209

Autoría

CARBO-MEIX, ANNA

GUIJARRO, FRANCESCA

WANG, LUOJUN

GRAU, MARTA

ROYO, ROMINA

FRIGOLA, GERARD

PLAYA-ALBINYANA, HERIBERT

BUHLER, MARCO M.

CLOT, GUILLEM

DURAN-FERRER, MARTI

LU, JUNYAN

GRANADA, ISABEL

BAPTISTA, MARIA-JOAO

NAVARRO, JOSE-TOMAS

ESPINTET, BLANCA

PUIGGROS, ANNA

TAPIA, GUSTAVO

BANDIERA, LAURA