Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3 ' regulatory region

Article

关键词: HEAVY-CHAIN LOCUS;    CLASS-SWITCH RECOMBINATION;    B-CELL DEVELOPMENT;    CHROMOSOMAL TRANSLOCATIONS;    V(D)J RECOMBINATION;    GENE AMPLIFICATION;    TRANSGENIC MICE;    DNA BREAKS;    END;    MECHANISM;   

DOI  :  10.1038/nature08633

来源: SCIE

【 摘 要 】

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)(1). 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)(2-4). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (C mu) exons, which are the first of several sets of CH exons ('C-H genes') within a CH locus that span several hundred kilobases (kb)(5,6). In mature B cells, CSR deletes C mu and replaces it with a downstream C-H gene(6). An intronic enhancer (iE mu) between the variable region exons and C mu promotes V(D)J recombination in developing B cells(7). 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(8-10). Transgenic mice bearing iE mu or Igh3' RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression(11-16). However, in many B-cell lymphomas, Igh-c-myc translocations delete iE mu and place c-myc up to 200 kb upstream of the Igh3' RR1. 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.

【 授权许可】

Free