Genomic Abnormalities Acquired in the Blastic Transformation of Splenic Marginal Zone B-cell Lymphoma

Abstract

Among 20 cases of typical splenic marginal zone lymphoma (SMZL), two cases had blastic transformation. The genetic mechanisms underlying the morphologic transformation were investigated by comparing genetic changes in initial and blastic phases. A complex karyotype including trisomy of 3q and genomic gain of 17q22-q24 was seen in both cases at diagnosis. However, the extra copy of 3q was lost during the transformation process in both tumors. Additionally, the Karpas 1718 cell line, which was derived from a patient with transformed SMZL and carried a trisomy of 3q, also evidenced the spontaneous loss of the extra 3q during the culturing process. Other acquired abnormalities observed exclusively in the transformation phase included amplification and/or translocation of bands 7p22-q22 and 19p13. These findings suggest that the loss of + 3q and the acquisition of other genomic imbalances may represent unique markers for the transformation process of SMZL. We hypothesize that the trisomy of 3q may correlate with the indolent nature of SMZL, and that the loss of this acquired abnormality leads to or accompanies the development of blastic tumors.

Molecular cytogenetic characterization of t(14;19)(q32;p13), a new recurrent translocation in B cell malignancies

“…In case 2, the breakpoint on chromosome 19 was found to lie between BAC clones RP11-347E20 and RP11-959O6, as the fluorescent signal from the former was seen on der (14), whereas the signal from the latter clone was seen on the der (19). After a few hybridizations, however, there was no material left to increase the resolution of our investigation, which mapped the breakpoint to a genomic region of 2 Mb.…”

“…Fosmid clones spanning BRD4 and AKAP8 were selected. Hybridization with the clones G248P84243B7 and G248P8276B1, which contain sequences from the BRD4 gene, gave three signals: on the normal chromosome 19, on the der (19), and on the der(14) (Fig. 3a); this demonstrates that BRD4 was split by the translocation.…”

“…Not surprisingly, on chromosome 14, we could identify the breakpoint to the variable region of IGH@ in both analyzed cases. The signal from clone RP5-998D24 mapping to the IGH@ constant region was retained on the der(14), whereas clones RP11-1145H5 and RP11-47P23, specific for the distal region of the IGH@ variable cluster, hybridized on the der(14) and the der (19), respectively, indicating that the breakpoint lay between the two clones. On chromosome 19, however, the breakpoint position varied between the two cases.…”

“…After a few hybridizations, however, there was no material left to increase the resolution of our investigation, which mapped the breakpoint to a genomic region of 2 Mb. When the clone containing the sequence for the BRD4 gene was hybridized to metaphase plates from this case, the sequences with which the probe hybridized were shown to be retained on the der (19), showing a more distal (about 2 Mb) breakpoint position than in case 1. In addition, in both cases, the involvement of the two oncogenes TCF3 (transcription factor 3, also known as E2A), located on 19p13, and BCL3 (B cell CLL/lymphoma 3), which maps to 19q13, was specifically tested for.…”

“…On chromosome 19, however, the breakpoint position varied between the two cases. In case 1, the FISH analysis pinpointed the breakpoint to inside the genomic region covered by BAC clone RP11-74L8 because on metaphase (19), and on the der (14). As the RP11-74L8 clone contains sequences of two different genes mapping to 19p13, BRD4 and AKAP8, additional FISH experiments were planned to discriminate between the possible involvement of these two genes.…”