Chromosomal translocations involving t(14;18)(q32;q21) and the chromosome 3q27 region are common in B-cell nonHodgkin lymphoma of germinal center cell origin. Grade 3B follicular lymphoma (FL), consisting almost exclusively of centroblasts, is a distinct subgroup of follicular lymphomas that has more in common clinically with the aggressive diffuse large B-cell lymphomas than with their indolent FL grade 1 and 2 counterparts. We studied the cytogenetic and molecular genetic aberrations by classic cytogenetics, polymerase chain reaction, Southern blot hybridization, and fluorescence in situ hybridization, with special emphasis on t(14;18), affecting bcl-2, and 3q27 rearrangement, affecting bcl-6, in 32 cases of FL grade 3B. Three distinctive subgroups were identified based upon the existence of breakpoint 3q27, a translocation t(14;18), or the absence of both. Group I involved a t(14;18) and no 3q27 aberrations (n ‫؍‬ 13); group II was without a t(14;18) and without 3q27 aberrations (n ‫؍‬ 9), but had other cytogenetic aberrations; and group III was without a t(14;18) but with aberrations involving 3q27 (n ‫؍‬ 10). None of the FL grade 3B cases harbored both a t(14;18) and 3q27 aberration. These results, in particular the finding of a mutual exclusiveness of bcl-2 and bcl-6 rearrangement, indicate at least 3 different pathways of oncogenesis in FL grade 3B. FL grade 3B with bcl-2 rearrangement probably is part of the same entity as the other follicular lymphomas (1, 2, 3A), whereas the cases with 3q27 abnormalities or other unrelated translocations are more closely related to the majority of diffuse large-cell lymphomas of germinal center cell origin. (Blood.

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Splenic marginal zone lymphoma (SMZL) is a rare non-Hodgkin's lymphoma that recently has been recognized as an entity. The first goal of this study was to identify potential chromosomal aberrations in this entity by cytogenetic analysis and comparative genomic hybridization (CGH). The second goal was to assess the frequency of 7q31-32 allelic imbalances in SMZL with primary involvement of the spleen and the typical immunophenotype (IgM+; IgD(dim); and CD5-, CD10-, and CD23-). We applied CGH and cytogenetics to 13 cases of SMZL with primary splenic involvement. By CGH, we found DNA copy number changes in 11 of 13 cases. Overall chromosomal gains were more frequent than chromosomal losses. Gains were most frequently detected for chromosome X, chromosome 3, and chromosome 18. Losses commonly involved chromosome 7 and chromosome 6.CGH and cytogenetic analysis showed a deletion in chromosome 7q31 in 4 cases. Loss of heterozygosity (LOH) analysis using three microsatellite markers located at 7q31 revealed LOH in 9 cases. Remarkably, 2 of the 4 cases that lacked a 7q31 deletion had an atypical immunophenotype because they were partially CD23 positive. The other 2 cases were not informative. The findings indicate that SMZL with primary splenic presentation and the typical IgM+, IgDdim, CD5-, CD10-, CD23- immunophenotype is characterized by the presence of deletions in chromosome 7q31-32.

Mantle cell lymphoma (MCL) is characterized by genetic instability and a poor prognosis. Many blastoid variants are (hypo)tetraploid and have an even worse prognosis. We investigated the role of signalling by mitogen-activated protein kinases (MAPKs) in MCL. As compared to normal tonsil B cells, MCL cells showed higher activation of the JNK MAPK in both an MAPK array and a sandwich ELISA assay. Immunohistochemistry showed overexpression of phospho (p)-JNK (Thr183/Tyr185) in 30 of 37 MCL cases. Inhibition of p-JNK with SP600125 resulted in growth arrest in all four MCL cell lines (Jeko-1, HBL-2, UPN-1, Granta-519), which could be partly reversed by the addition of CD40L and IL-4. Furthermore, SP600125 led to G2/M phase arrest on day 1 and a striking increase in endoreduplication on day 2 and day 3, which was confirmed by karyotype analysis. G2/M arrest was associated with down-regulation of EGR1 and p21 protein expression. SP600125-induced polyploidy could be blocked by the BCL-2 inhibitor YC137. These data suggest that constitutive JNK activity is necessary to promote proliferation and maintain diploidy in MCL. JNK inhibition leads to cell cycle deregulation and endoreduplication, mimicking the tetraploid state seen in a subset of MCL cases. Thus, our data also provide an experimental model to study polyploid MCL cells.