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...

IgD on normal B lymphocytes usually is co-expressed with IgM. A minority of normal plasma cells and rare B cell malignancies express exclusively IgD (IgM-IgD+). The low frequency has been explained by the lack of a recognizable switch region within the C mu-C delta intron. We analyzed four cases of IgM-IgD+ hairy cell leukemia (HCL) by Southern (DNA) blot analysis and identified two cases with a recombinatorial event within the C mu-C delta intron and deletion of C mu. DNA sequence analysis of junctional regions showed that S mu or the immediate upstream region was used as a donor site and that the C mu-C delta intronic sigma delta region was used as acceptor site. Using polymerase chain reaction, we subsequently analyzed whether similar S mu-sigma delta recombinations occur in normal tonsils containing IgM-IgD+ plasma cells. Multiple products with a size range of 200-800 base pairs were detected in all four individuals, suggesting clustering of acceptor sites within sigma delta. Sequence analysis of three cloned products showed S mu-sigma delta recombinations similar those observed in HCL. The sigma delta region contains a relatively high content of pentameric repeats with an extremely G-rich area and appears to function as a vestigial switch recombination site in normal and neoplastic IgM-IgD+ B cells.