title: Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Gostissa
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Yan
authors.forename: Julia M
authors.initials: JM
authors.lastname: Bianco
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.forename: Eric
authors.initials: E
authors.lastname: Pinaud
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D056905:Chromosome Breakpoints; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics*; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics*; D017578:Immunoglobulin Class Switching / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions