A novel t(3;8)(q27;q24.1) simultaneously involving both the BCL6 and MYC genes in a diffuse large B-cell lymphoma

Diffuse large B-cell lymphomas (DLBCLs) are a clinically and biologically heterogeneous group of hematologic malignancies. Specific genetic aberrations underlie some of this heterogeneity. These genetic events include distinct and separate translocations resulting in the dysregulated expression of either BCL6 protein with the t(3;14)(q27;q32) or c-MYC protein with the t(8;14)(q24;q32), as a consequence of the juxtaposition of these oncogenes with heterologous promoters or enhancers, such as those of the immunoglobulin heavy chain gene. Here, we report the case of a patient with DLBCL with a unique t(3;8)(q27;q24.1) that involves the BCL6 and MYC genes. We know of no previous report of this translocation in DLBCL, which simultaneously affects two key genes implicated in lymphomagenesis and may reflect a novel genetic mechanism in neoplastic transformation.     

Four cases of follicular lymphoma with t(14;18)(q32;q21) and t(3;4)(q27;p13) with LAZ3 (BCL6) rearrangement.

We report four cases of follicular lymphoma with both t(14;18)(q32;q21) and the newly characterized t(3;4)(q27;p13). Molecular investigation confirmed LAZ3 (BCL6) rearrangement for all patients. The 3q27 aberrations have been rarely described in low-grade lymphomas and may represent secondary events whose implication remains to be elucidated.     

A novel t(6;14)(q25-q27;q32) in acute myelocytic leukemia involves the BCL11B gene

We report a case of essential thrombocythemia (ET) in a 39-year-old woman who developed myelofibrosis at follow-up. The cytogenetic and fluorescence in situ hybridization analyses revealed a pathologic clone with the following previously unreported karyotype: 46,XX,ins(4;11)(q27;q24q21). We cannot conclude that the presence of this inverted insertion was associated with the overproduction of platelets, but documentation of more cases with chromosomal abnormalities and ET should lead to identifying different candidate genes involved in the neoplastic growth.     

Reciprocal t(14;19)(q32.3;q13.1) in a patient with B-cell lymphoma

A patient with B-cell lymphoma with a chromosome rearrangement of t(14;19)(q32.3;q13.1) is reported. This patient had leukemic features and an aggressive clinical course. The histopathologic diagnosis was malignant lymphoma, small noncleaved cell. Chromosome analysis of the cells from a cervical lymph node and peripheral blood showed a reciprocal translocation between chromosome 14 with a break at band q32.3 and chromosome 19 with a break at band q13.1, to which the bcl-3 gene has been mapped. Monoclonal rearrangement of the JH gene was detected by Southern blot analysis. However, we could not detect rearrangement of the bcl-3 gene. This case also had a t(2;8)(q13;q24.1), but the c-myc gene remained in its germline. This is the first case with the reciprocal t(14;19) and 8q24 chromosomal breakpoint in a B-cell lymphoid malignancy.     

Intravascular large B-cell lymphoma associated with a near-tetraploid karyotype, rearrangement of BCL6, and a t(11;14)(q13;q32)

Chromosome analysis of a patient with intravascular large B-cell lymphoma (IVL) revealed a complex, near-tetraploid karyotype with 83 chromosomes. Abnormalities included a t(11;14)(q13;q32), which was confirmed with both interphase fluorescence in situ hybridization (FISH) using an IGH/cyclin D1 dual-color, dual-fusion probe set and cyclin D1 immunohistochemical analysis. Abnormality of 3q was also evident. Interphase FISH analysis with a dual-color, break-apart probe set confirmed rearrangement of BCL6. To our knowledge, this is the first report of these abnormalities in IVL.     

t(18;22)(q21;q11) with rearrangement of BCL2 as a possible secondary change in a lymphocytic lymphoma

We report a lymphocytic lymphoma showing a combination of two characteristic neoplasia-associated chromosomal changes: trisomy 12, commonly observed in chronic lymphocytic leukemia and lymphocytic lymphoma, and t(18;22)(q21;q11), a variant form of the t(14;18)(q32;q21) found in most follicular lymphomas. Southern blot analysis was performed using probes for the 5' end of the BCL2 gene (18q21) and for the J lambda as well as C lambda immunoglobulin genes (22q11). With these two probes, a unique rearranged fragment was detected. Thus the t(18;22)(q21;q11) can be considered as a variant translocation of t(14;18)(q32;q21). The karyotypic analysis supports the assumption that in our case trisomy 12 occurred first, and t(18;22) appeared during tumor progression as part of the clonal evolution. This is at variance with the typical t(14;18), which has never been found to occur as a secondary change.     

A novel t(2;3)(p11;q27) in a case of follicular lymphoma

Rearrangement of the BCL6 gene is found in follicular lymphomas and in diffuse large B cell lymphomas of follicular center cell origin. The breakpoints cluster mainly in a region spanning the first noncoding exon of the gene (the major breakpoint region). A second breakpoint cluster has also been identified upstream of the first BCL6 noncoding exon (the alternative breakpoint region [ABR]). To date, eight different rearrangements involving the ABR have been reported. Here, we describe a novel rearrangement involving a t(2;3)(p11;q27) translocation that affects the ABR in an unusual combination with the IGK locus.     

Reciprocal translocation t(3;12)(q27;q13) in lipoma

A reciprocal translocation, t(3;12)(q27;q13), was found as the sole karyotypic abnormality in an intramuscular lipoma. The morphology of the derivative 3q+ was strongly reminiscent of the large ring marker we have previously described in three other lipomas, indicating a pathway through which the rings may have arisen. These data, combined with the previous preliminary report by Turc-Carel et al. of a similar t(3;12) in another lipoma strongly suggest that this rearrangement may be a characteristic cytogenetic marker in benign lipogenic tumors.     

A t(1;9)(q23.3 approximately q25;q34) affecting the ABL1 gene in a biphenotypic leukemia

Recurring chromosome translocations, which are found in leukemia, can result in the inappropriate expression of oncogenes or in the formation of chimeric genes that code for structurally and functionally abnormal proteins. The chromosomal t(1;9)(q23.3 approximately q25;q34) was found in a patient with biphenotypic leukemia. Fluorescence in situ hybridization (FISH) analysis revealed that the break on chromosome 9 occurred in the ABL1 gene. The breakpoint on chromosome 1 occurred distal to the PBX1 gene at 1q23.3, as shown by FISH using BAC RP11-503N16 and RP11-403P14, which flank the PBX1 locus; hence, the ABL1 gene can be fused with another gene distal to PBX1 gene.     

t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

Hodgkin/Reed-Sternberg (HRS) cells represent the malignant fraction of infiltrated lymph nodes in Hodgkin lymphoma (HL). Although HRS cells display multiple chromosomal aberrations, few are recurrent and the targeted genes unknown. However, understanding the pathology of HL and developing rational therapies may well require identifying putative deregulated genes. Here, we analyzed the karyotype of the well-defined HL cell line L-1236 by spectral karyotyping and identified multiple abnormalities, therein, notably t(4;8)(q27;q24) which includes two breakpoint regions previously highlighted in HL. Target genes at 4q27 and 8q24 were shortlisted by high density genomic arrays and fluorescence in situ hybridization. Expression analysis of candidate target genes revealed conspicuous activation of phosphodiesterase PDE5A at 4q27 and inhibition of homeobox gene ZHX2 at 8q24. Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed against PDE5A and concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicating PDE5A as an oncogene. Expression profiling of L-1236 cells following siRNA-mediated knockdown of ZHX2 showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity of ZHX2. Downstream genes included STAT1 and several STAT1-target genes, indicating activation of STAT1-signaling by ZHX2 as analyzed by RQ-PCR and western blot. Taken together, we have identified a novel aberration with recurrent breakpoints in HL, t(4;8)(q27;q24), which activate PDE5A and repress ZHX2, deregulating apoptosis, differentiation, and STAT1-signaling in HL cells.     

Nodal marginal zone B-cell lymphoma with a novel t(X;5)(q28;q22): conventional and molecular cytogenetic analysis

Cytogenetic studies provide important information for the diagnosis and classification of malignant lymphomas that in some cases also has prognostic significance. Furthermore, the investigation of isolated novel cytogenetic findings in malignant lymphoma has led to the discovery of many important oncogenes and tumor suppressor genes. For this reason, a case of nodal marginal zone B-cell lymphoma in a 72-year-old woman is described in which analysis by conventional and molecular cytogenetic techniques demonstrated the presence of a t(X:5)(q28;q22) as the sole chromosomal abnormality. This translocation has not been previously reported in the literature.