604

BCL6

BCL5|BCL6A|LAZ3|ZBTB27|ZNF51;B-cell CLL/lymphoma 6;BCL6;B-cell CLL/lymphoma 6

B-cell lymphoma 5 protein|B-cell lymphoma 6 protein|B-cell lymphoma 6 protein transcript|BCL-5|BCL-6|cys-his2 zinc finger transcription factor|lymphoma-associated zinc finger gene on chromosome 3|protein LAZ-3|zinc finger and BTB domain-containing protein

3q27

protein-coding

BACKGROUND: Follicular lymphoma in childhood is rare. The authors present four unusual primary follicular lymphomas of the testis in children. METHODS: tumor tissue was evaluated using light microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction (PCR) for immunoglobulin heavy chain (IgH) and bcl-2 gene rearrangements. Southern blot and immunohistochemical analyses were used to detect bcl-6 gene rearrangements and protein expression, respectively. RESULTS: Four young boys ranging in age from 3 to 10 years were diagnosed with Stage IE follicular large cell lymphoma (Grade 3). A B-cell phenotype was documented in ALL four cases; monoclonality was confirmed in threecases by demonstration of light chain restriction or clonal IgH gene rearrangement. None of the lymphomas expressed Bcl-2 or p53 protein, and bcl-2 gene rearrangements were not found in the three lymphomas studied. In contrast, Bcl-6 protein was expressed by ALL three lymphomas studied, and a bcl-6 gene rearrangement was detected in the one case analyzed by Southern blot. ALL four boys were treated by orchiectomy and combination chemotherapy and are alive withno evidence of disease 18-44 months following their initial diagnoses. CONCLUSIONS: Follicular lymphomas may rarely occur as primary testicular tumors in prepubertal boys and, when localized, appear to be associated with a favorable prognosis. In contrast to follicular lymphoma in adults, pediatric follicular lymphomas of the testis are usually of large cell type (Grade 3) and lack bcl-2 or p53 abnormalities. The identification, in one case, of a bcl-6 gene rearrangement suggests an alternate molecular pathogenesis for pediatric follicular lymphoma.

Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, that is, the translocation t(8;14)(q24;q32) or its variants. However, diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B-cell lymphomas such as diffuse large B-cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this review the 'Mitelman Database of Chromosome Aberrations in cancer,' harboring the majority of ALL published neoplasia-related karyotypes, was explored to define a cytogenetic profile of 'true' BL. This core subset of BL showed a very low complexity of chromosomal abnormalities with 40% of the cases having the IG-MYC fusion as the sole abnormality. In the remaining cases, additional recurrent but partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. Within the core subset, no differences were found between pediatric and adult patients. In addition, the genetic profile of the core subset was significantly different from BL with an 8q24 breakpoint not affecting one of the three immunoglobulin loci, BL with a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1, additionallyto a breakpoint at 8q24/MYC, and from other morphological types of lymphomas with an 8q24/MYC breakpoint. These groups showed a higher cytogenetic complexity thanthe core subset of BL. BL without a detectable 8q24/MYC breakpoint might be heterogeneous and deserves further studies. We suggest that, concordant with theWHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. In addition, a high number of nonspecific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL.

Neuroblastoma (NB) is the most common extracranial solid neoplasm of infancy andchildhood. Whereas most low-risk patients do well, children with high-risk tumors often fail intensive treatment. Identification of novel biomarkers is critical to improve prognostication, tailor therapy, and develop new therapeutic targets. Differential RNA-level expression between tumor cells with neuroblastic (N-type)and Schwannian stromal (S-type) phenotypes was used to identify genes of potential interest based on tumor cell type-specific regulation. Gene expressionmicroarray analysis revealed marked differences between N-type and S-type cells in their levels of BCL6 messenger RNA, a transcriptional regulator overexpressedin a variety of hematopoietic malignancies. S-type cells express higher levels of Bcl6 RNA and protein than N-type, and protein levels are significantly limited by proteasome function. An NB tumor tissue microarray linked to clinicopathologic data was immunohistochemically stained to measure Bcl6 protein levels. Bcl6 was detected in both the neuroblastic and Schwannian stromal regions, as distinguished histologically, and correlated with outcome. We found that expression in neuroblastic regions differentiates outcomes, in that Bcl6 expression in neuroblastic regions is associated with increased time to relapse and increased overall survival compared with absent expression in neuroblastic regions, regardless of Schwannian stromal expression. Thus, our findings suggestthat Bcl6 may be useful as a prognostic marker and might represent a potential therapeutic target for high-risk NB.

The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes ofDLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.