Dataset Information

3'Igh enhancers hs3b/hs4 are dispensable for Myc deregulation in mouse plasmacytomas with T(12;15) translocations.

ABSTRACT: Myc-deregulating T(12;15) chromosomal translocations are the hallmark cytogenetic abnormalities of murine plasmacytomas (PCTs). In most PCTs, the immunoglobulin heavy chain (Igh) locus is broken between the E? enhancer and the 3' regulatory region (3'RR), making the latter the major candidate for orchestrating Myc deregulation. To elucidate the role of the Igh3'RR in tumorigenesis, we induced PCTs in Bcl-xL-transgenic mice deficient for the major Igh3'RR enhancer elements, hs3b and hs4 (hs3b-4^-/-). Contrary to previous observations using a mouse lymphoma model, which showed no tumors with peripheral B-cell phenotype in hs3b-4^-/- mice, these animals developed T(12;15)-positive PCTs, although with a lower incidence than hs3b-4^+/+ (wild-type, WT) controls. In heterozygous hs3b-4^+/- mice there was no allelic bias in targeting Igh for T(12;15). Molecular analyses of Igh/Myc junctions revealed dominance of S? region breakpoints versus the prevalence of S? or S? in WT controls. Myc expression and Ig secretion in hs3b-4^-/- PCTs did not differ from WT controls. We also evaluated the effect of a complete Igh3'RR deletion on Myc expression in the context of an established Igh/Myc translocation in ARS/Igh11-transgenic PCT cell lines. Cre-mediated deletion of the Igh3'RR resulted in gradual reduction of Myc expression, loss of proliferative activity and increased cell death, confirming the necessity of the Igh3'RR for Myc deregulation by T(12;15).

SUBMITTER: Kovalchuk AL

PROVIDER: S-EPMC6195379 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

3'Igh enhancers hs3b/hs4 are dispensable for Myc deregulation in mouse plasmacytomas with T(12;15) translocations.

Kovalchuk Alexander L AL Sakai Tomomi T Qi Chen-Feng CF Du Bois Wendy W Dunnick Wesley A WA Cogné Michel M Morse Herbert C HC

Oncotarget 20181002 77

Myc-deregulating T(12;15) chromosomal translocations are the hallmark cytogenetic abnormalities of murine plasmacytomas (PCTs). In most PCTs, the immunoglobulin heavy chain (Igh) locus is broken between the Eμ enhancer and the 3' regulatory region (3'RR), making the latter the major candidate for orchestrating Myc deregulation. To elucidate the role of the Igh3'RR in tumorigenesis, we induced PCTs in Bcl-xL-transgenic mice deficient for the major ...[more]

PMID: 30349647

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Project description:B-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.

Dataset Information

3'Igh enhancers hs3b/hs4 are dispensable for Myc deregulation in mouse plasmacytomas with T(12;15) translocations.

Publications

3'<i>Igh</i> enhancers hs3b/hs4 are dispensable for <i>Myc</i> deregulation in mouse plasmacytomas with T(12;15) translocations.

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