Novel Control Motif Cluster in the IgH δ-γ3 Interval Exhibits B Cell-Specific Enhancer Function in Early Development

Mundt, Cornelia; Nicholson, I.; Zou, Xiangang; Попов, А. В.; Ayling, Christine; Brüggemann, Marianne

doi:10.4049/jimmunol.166.5.3315

Cited by 18 publications

(13 citation statements)

References 91 publications

(75 reference statements)

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“…3) A defined region between the C␦ and C␥3 coding exons (E␦-␥3) in the human IgH locus has been shown to potentiate transcription from transgenic reporter genes in mouse precursor B cells. This putative enhancer, which may have a murine homolog, also functions cooperatively with E in reporter assays (47). The mice reported in the present study, which harbor deletions in the two known D H J H regulatory elements, will be important reagents for deciphering the complex interplay of promoters and enhancers that activate IgH gene assembly and trigger the B cell developmental program.…”

Section: Discussionmentioning

confidence: 67%

Regulation of IgH Gene Assembly: Role of the Intronic Enhancer and 5′DQ52 Region in Targeting DHJH Recombination

Afshar

Pierce

Bolland

et al. 2006

The Journal of Immunology

107

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The assembly of Ag receptor genes by V(D)J recombination is regulated by transcriptional promoters and enhancers which control chromatin accessibility at Ig and TCR gene segments to the RAG-1/RAG-2 recombinase complex. Paradoxically, germline deletions of the IgH enhancer (Eμ) only modestly reduce DH→JH rearrangements when assessed in peripheral B cells. However, deletion of Eμ severely impairs recombination of VH gene segments, which are located over 100 kb away. We now test two alternative explanations for the minimal effect of Eμ deletions on primary DH→JH rearrangement: 1) Accessibility at the DHJH cluster is controlled by a redundant cis-element in the absence of Eμ. One candidate for this element lies 5′ to DQ52 (PDQ52) and exhibits promoter/enhancer activity in pre-B cells. 2) In contrast to endpoint B cells, DH→JH recombination may be significantly impaired in pro-B cells from enhancer-deficient mice. To elucidate the roles of PDQ52 and Eμ in the regulation of IgH locus accessibility, we generated mice with targeted deletions of these elements. We report that the defined PDQ52 promoter is dispensable for germline transcription and recombination of the DHJH cluster. In contrast, we demonstrate that Eμ directly regulates accessibility of the DHJH region. These findings reveal a significant role for Eμ in the control mechanisms that activate IgH gene assembly and suggest that impaired VH→DHJH rearrangement in enhancer-deficient cells may be a downstream consequence of the primary block in DH→JH recombination.

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Section: Discussionmentioning

confidence: 67%

Regulation of IgH Gene Assembly: Role of the Intronic Enhancer and 5′DQ52 Region in Targeting DHJH Recombination

Afshar

Pierce

Bolland

et al. 2006

The Journal of Immunology

107

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“…It is further conceivable that C H deletions effect a fine-tuning of Myc expression by, first, reducing the genomic distance between Myc and the 3Ј-C␣ enhancers and, second, eliminating control elements of transcription that reside in the long intervening regions between C H loci, 21 e.g., in the C␦/C␥3 interval. 22 The recent development of AID knockout mice in Honjo's laboratory 23 has offered a unique opportunity to decide among these possibilities, because it will permit us to assess T(12;15) and PCT development in mice that are unable to perform isotype switching. We hope that genetic studies of this sort will be helpful to better our understanding of the significance of C H deletions on der (14) in chronic lymphocytic leukemia, 9 sporadic Burkitt's lymphoma, 8 follicular lymphoma 10,24 and MALT lymphoma 25 20-bp sequence flanking the junction site.…”

Section: Resultsmentioning

confidence: 99%

Isotype switch‐mediated C_H deletions are a recurrent feature of Myc/C_H translocations in peritoneal plasmacytomas in mice

Kovalchuk

Janz

2002

Intl Journal of Cancer

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Oncogene activating chromosomal translocations that interrupt IGH switch (S) regions at 14q32 are thought to be caused by misguided IGH isotype switching in postgerminal center B-cell lymphomas and plasma cell myelomas in humans. Aberrant switching also seems to be involved in altering the fine structure of the translocation in some of these tumors, but the significance of these changes is not known. Here we report on 3 cases of IL-6 transgenic mouse plasmacytomas (PCT) that harbor T(12;15) translocations that had been modified by frustrated switch attempts that result in C H deletions. When considered together with 6 similar cases of PCT described previously, our observations suggest that secondary deletions in C H are a regular feature in the molecular evolution of T(12;15) translocations and, thereby, in the progression of PCT. We propose that the T(12;15)؉ mouse PCT offers a uniquely valuable model system for elucidating the dual role of abnormal isotype switching in causation and 'remodeling' of chromosomal translocations. © 2002 Wiley-Liss, Inc. Aberrant isotype switching in human germinal center B cells can lead to chromosomal translocations that recombine IGH switch (S) regions at 14q32 with a variety of oncogenes. Translocation breakpoints in S regions were first detected in MYC-activating t(8;14)(q24;q32) exchanges in sporadic Burkitt's lymphoma and later found in B-cell chronic lymphocytic leukemia [t(14; 19)(q32;q13), BCL3], diffuse large-cell lymphoma [t(3;14)(q27; q32), BCL6; t(10;14)(q24;q32), NFKB2; t(1;14)(q21;q32), MUC1], lymphoplasmacytoid lymphoma [t(9;14)(p13;q32), PAX5] and, with a surprising diversity, multiple myeloma [t(11;14)(q13;q32), CCND1 (cyclin D1); t(4;14)(p16.3;q32), FGFR3 and MMSET; t(14;16)(q32;q23), C-MAF; t(6;14)(p25;q32), IRF4; t(6;14)(p21; q32), CCND3 (cyclin D3)]. [1][2][3] The uniform location of all these breakpoints in S regions strongly implicates misguided IGH isotype switch recombination as an important catalyst of recurrent translocations in postgerminal center B-cell tumors in humans.It is generally less appreciated that aberrant isotype switching can also be involved in some human B and plasma cell tumors in the secondary modification of the fine structure of translocation on the derivative chromosome 14 (der 14). Unproductive switch attempts can cause additional chromosomal breaks that may result in transpositions, 4 complex translocations and amplifications 5,6 and sometimes destabilization of the entire der (14). 7 Another outcome of switching is deletions within the Ig heavy-chain gene cluster, C H . These may occur in the vicinity of the translocation breakpoint if translocation takes place in a S region 8,9 or hundreds of kilobases distant to the translocation breakpoint if translocation occurs far upstream of C H in the V H region. 10 It is not known if the isotype switch-mediated refinement of IGH breakpoint regions plays a role in the progression of human B-cell tumors; however, new insights could be obtained if this process could be studied in a gene...

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“…The crucial importance of the Myc-Ea interaction for Myc deregulation in plasma cell tumors has been clearly shown (12). The in vivo relevance of the Myc-Ey interaction has been recently noted by the surprising observation that EA is dispensable for MYC expression and lymphomagenesis in the YAC-MYC mouse (11), in which EA can apparently be substituted for by the Ey enhancer (49). Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Insertion of c-MycintoIghInduces B-Cell and Plasma-Cell Neoplasms in Mice

Park¹,

Kim²,

Tessarollo³

et al. 2005

Cancer Res

109

133

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We used gene targeting in mice to insert a His 6 -tagged mouse c-Myc cDNA, MycHis , head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5V of the intronic enhancer, EA. The insertion of Myc His mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, MycHis transgenic mice developed Bcell and plasma neoplasms, such as IgM + lymphoblastic B-cell lymphomas, Bcl-6 + diffuse large B-cell lymphomas, and CD138 + plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed Myc His , and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of Myc His , suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19ArfMdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that Myc His insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Mycactivating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation. (Cancer Res 2005; 65(4): 1306-15)

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Novel Control Motif Cluster in the IgH δ-γ3 Interval Exhibits B Cell-Specific Enhancer Function in Early Development

Cited by 18 publications

References 91 publications

Regulation of IgH Gene Assembly: Role of the Intronic Enhancer and 5′DQ52 Region in Targeting DHJH Recombination

Regulation of IgH Gene Assembly: Role of the Intronic Enhancer and 5′DQ52 Region in Targeting DHJH Recombination

Isotype switch‐mediated C_H deletions are a recurrent feature of Myc/C_H translocations in peritoneal plasmacytomas in mice

Insertion of c-MycintoIghInduces B-Cell and Plasma-Cell Neoplasms in Mice

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Novel Control Motif Cluster in the IgH δ-γ3 Interval Exhibits B Cell-Specific Enhancer Function in Early Development

Cited by 18 publications

References 91 publications

Regulation of IgH Gene Assembly: Role of the Intronic Enhancer and 5′DQ52 Region in Targeting DHJH Recombination

Regulation of IgH Gene Assembly: Role of the Intronic Enhancer and 5′DQ52 Region in Targeting DHJH Recombination

Isotype switch‐mediated CH deletions are a recurrent feature of Myc/CH translocations in peritoneal plasmacytomas in mice

Insertion of c-MycintoIghInduces B-Cell and Plasma-Cell Neoplasms in Mice

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Isotype switch‐mediated C_H deletions are a recurrent feature of Myc/C_H translocations in peritoneal plasmacytomas in mice