Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region.
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.
Gostissa
Monica
M
Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Yan
Catherine T
CT
Bianco
Julia M
JM
Cogné
Michel
M
Pinaud
Eric
E
Alt
Frederick W
FW
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*
D020413:3' Untranslated Regions