MALT B cell lymphomas with t(1;14)(p22;q32) showed a recurrent breakpoint upstream of the promoter of a novel gene, Bcl10. Bcl10 is a cellular homolog of the equine herpesvirus-2 E10 gene: both contain an amino-terminal caspase recruitment domain (CARD) homologous to that found in several apoptotic molecules. Bcl10 and E10 activated NF-kappaB but caused apoptosis of 293 cells. Bcl10 expressed in a MALT lymphoma exhibited a frameshift mutation resulting in truncation distal to the CARD. Truncated Bcl10 activated NF-kappaB but did not induce apoptosis. Wild-type Bcl10 suppressed transformation, whereas mutant forms had lost this activity and displayed gain-of-function transforming activity. Similar mutations were detected in other tumor types, indicating that Bcl10 may be commonly involved in the pathogenesis of human malignancy.
region, is the pathologic target. However, by molecular cloning of t(2;14)(p13;q32.3) from 3 cases of aggressive B-cell chronic lymphocytic leukemia (CLL)/immunocytoma, this study has shown clustered breakpoints on chromosome 2p13 immediately upstream of a CpG island located about 300 kb telomeric of REL. This CpG island was associated with a Krü ppel zinc finger gene (BCL11A), which is normally expressed at high levels only in fetal brain and in germinal center B-cells. There were 3 major RNA isoforms of BCL11A, differing in the number of carboxy-terminal zinc fingers. All 3 RNA isoforms were deregulated as a consequence of t(2;14) (p13;q32.3). BCL11A was highly conserved, being 95% identical to mouse, chicken, and Xenopus homologues. BCL11A was also highly homologous to another gene ( IntroductionMany subtypes of malignancy are associated with specific chromosomal translocations, which play a pivotal role in the pathogenesis of disease. In the leukemias and lymphomas of mature B-cells, these frequently involve the immunoglobulin (IG) loci and result in deregulated expression of the translocated oncogene, due, in part, to the presence of potent B cell-specific transcriptional enhancers within the IG loci. 1 All the common IG translocations have been cloned. Paradigms include the deregulation of cyclin D1 by t(11;14)(q13;q32.3), found in all cases of mantle cell lymphoma; BCL2 by t(14;18)(q32.3;q21.3), found in 80% of follicular lymphoma; and MYC by t(8;14)(q24.1;q32.3) and variant translocations in all cases of Burkitt lymphoma. 1 On the basis of cytogenetics alone, several rare, but nonetheless recurrent IG translocations remain to be cloned, principally in aggressive large-cell B-NHL 2 ; their molecular cloning continues to allow the isolation of novel dominant oncogenes and to define new pathogenic mechanisms. 1,[3][4][5][6] Chromosomal translocation t(2;14) (p13;q32.3) is one example and has been reported in a variety of B-cell malignancies ranging from B-cell precursor acute lymphoblastic leukemia to myeloma. This translocation is frequently the sole cytogenetic abnormality within the neoplastic clone (Watson et al,7 Geisler et al, 8 Sonoki et al, 9 and http://cgap.nci.nih.gov/ Chromosomes/Mitelman). We report here the recurrent involvement and deregulated expression of a Krüppel zinc finger gene, BCL11A, in 4 cases of B-cell malignancy with t(2;14)(p13;q32.3). Patients, materials, and methods Patient materialFour patients with B-cell malignancies and t(2;14)(p13;q32) were studied. Patient material was studied after obtaining written informed consent and local ethical committee approval. Two unusual pediatric patients with CLL (referred to here as patients AS and LH) who exhibited this translocation have been reported on previously 10 ; the translocation breakpoints in these 2 cases were cloned using bacteriophage cloning. 11 In addition, 2 adult patients identified from our cytogenetic databases with identical translocations were also studied. Patient 3 was a previously well 62-year-old female who pres...
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