The BCL11 gene family: involvement of BCL11A in lymphoid malignancies

Abstract

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...

Proteomics of acute myeloid leukaemia: cytogenetic risk groups differ specifically in their proteome, interactome and post-translational protein modifications

“…B-cell CLL lymphoma/leukaemia 11A identified as a differential target of CK functions as a myeloid and B-cell proto-oncogene. Its high expression in AML points towards a probable role in leukemogenesis and haematopoiesis (Satterwhite et al, 2001). In our validation experiments, we detected the differential expression of IAP in t(8;21) patients and AML1/ETO-inducible system.…”

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

“…Two oncogenes involved in lymphomagenesis, REL and BCL11A, are located in this region. 12,40 In fact, the overexpression of both genes was observed in all patients who had DLBCL with 2p amplification by means of real-time quantitative PCR. 12 In the current study, we were able to identify the minimally targeted genomic regions of 2p16.1 amplification, where REL (and not BCL11A) was located, as the only candidate oncogene.…”

Somatic stem cells and the origin of cancer

“…In early stages, both PU.1 and Ikaros control the balance between myeloid or lymphoid commitment of MMPs through regulation of different signaling receptors (FLT3, c-KIT and IL-7R) [157][158][159] . More committed, earliest B cell progenitor transition to pro-B cell depends on addi-tional transcription factors (E2A, EBF, PAX5 and BCL11A), which coordinately activate appropriate Bcell expression programs and immunoglobulin heavychain gene rearrangements [160][161][162][163][164][165] . (fig.…”

“…Notably, many of the genes involved in the lymphocyte developmental network are targeted in such chromosomal translocations, namely PAX5, OBF1, BCL11A, BCL6, IRF4/MUM1, Ikaros, NOTCH1 and FOXP1 (table 1) 155,164,183,[185][186][187][188][189][190][191] . Other regulatory genes are also altered through alternative genetic mechanisms, such as gene amplification of the NF-κB family gene REL, activating mutation of NOTCH1 and inactivating mutation of BLIMP1 119,[192][193][194] .…”