The IgH 3′ regulatory region and its implication in lymphomagenesis

Abstract

The 3 0 regulatory region (3 0 RR) located downstream of the IgH gene is the master element that controls class switch recombination and sustains high-level transcription at the plasma-cell stage. This latter role suggests that the 3 0 RR may be involved in oncogene deregulation during the frequent IgH translocation events associated with B-cell malignancies. A convincing demonstration of the essential contribution of 3 0 RR in lymphomagenesis has been provided by transgenic animal models. The mouse 3 0 RR shares a strong structural homology with the regulatory regions located downstream of each human Ca gene. Mouse models exploring the role of the 3 0 RR in B-cell physiology and in malignancies should provide useful indications about the pathophysiology of human cell lymphocyte proliferation.Key words: B cells . Cellular proliferation . Oncology IntroductionDuring precursor B-cell differentiation, genes encoding heavy (H) and light chains of an Ig molecule are somatically assembled from germline DNA. This process, named V(D)J recombination, occurs in the bone marrow prior to antigenic challenge. In germinal centers during the antigen-dependent stages, variable (V) regions become the target of somatic hypermutation (SHM) in activated B cells allowing the generation of high-affinity Ig. In mature B cells, class switch recombination (CSR) deletes the constant (C) m region and replaces it with a downstream C H gene. This enables B cells to express various Ig isotypes but still retain antigen specificity. Once activated, B cells differentiate into Ig-secreting plasma cells. During B-cell development all these events (V(D)J recombination, SHM, CSR, Ig synthesis) are coupled with transcriptional accessibility of the IgH loci. IgH transcription is controlled by the functional interactions of multiple promoters, enhancers and insulators spread among the 2.5 megabases of the locus. Among them, the upstream Em enhancer and the 3 0 regulatory region (3 0 RR) stand out as major players. Chromosomal translocations linking oncogenes to these elements are often implicated as the cause of B-cell malignancies. In this brief review of relevant knock-out and transgenic mouse models, we underline how the physiological functions of the IgH 3 0 RR might translate into a critical role in oncogene deregulation during lymphomagenesis.From the El cis-activating element to the 3 0 RR Thirty years ago, Em was the first transcriptional enhancer discovered upstream of the m gene (Fig. 1A) [1][2][3]. Em deletion in mice confirmed its role in controlling access to the locus prior to D-J recombination, but, moreover, showed its dispensability for CSR and SHM [4]. Eventually, several more transcriptional enhancers were identified at the 3 0 end of the locus. hs1,2 was identified 12.5-kb downstream of the mouse Ca (Fig. 1A) 3306Mini-Review differentiation stages, while hs4 is active during the pre-B-cell stage and throughout B-cell development (Fig. 1A) [8,9]. The modest activity of each of the 3 0 RR elements, however, contributes to a synergic...

Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma

“…13,26 However, IgH-3'RRs also regulates IgH expression, somatic hypermutation and class switch in the wild-type IgH allele. 27, 28, 29, 30, 31 Therefore, we reasoned that intratumoral heterogeneity of BCL2 expression in lymphoma cells should at least in part originate from differential mRNA transcription from the t(14;18)-translocated allele, and correlate with IgH since both are controlled by IgH-3'RRs regions. To analyze the BCL2 and IgH mRNA transcripts in single lymphoma cells, we implemented an smFISH technique that allows absolute measurements of the number of mRNA molecules in individual cells.…”

Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting

“…Genomic rearrangements involving IGH are believed to lead to overexpression of the partner oncogene by placing it under the regulatory control of the IGH locus. 18 Expression levels of MMSET/FGFR3 (4p16.3) and CCND1 genes were successfully measured for 449 MM cases ( Figure 6C). As depicted in Figure 6C, we observed overexpression of both CCND1/FGFR3 and CCND1 genes in samples harboring the respective rearrangements.…”

Enhancers Located in Heavy Chain Regulatory Region (hs3a, hs1,2, hs3b, and hs4) Are Dispensable for Diversity of VDJ Recombination

“…The IgH 3Ј regulatory region (3ЈRR) 4 that encompasses the four transcriptional enhancers hs3a, hs1,2, hs3b, and hs4 has been reported as the master element controlling class switch recombination (2,9) and is also important for oncogene deregulation in B-cell lymphomagenesis (10,11). Whereas physical chromosomal interactions have been reported in pro-B-cells between the 5Ј E enhancer and the 3ЈRR (12,13) and whereas GFP transgenic mice highlighted that combination of 5Ј E and the 3ЈRR mimics the B-specific endogenous expression pattern of IgH genes from pro-B-cells to mature B-cells (14,15), the potential contribution of the 3ЈRR to V(D)J recombination control has never been studied.…”