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Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region

M. Gostissa,Catherine T. Yan,Julia M Bianco,M. Cogné,E. Pinaud,F. Alt

Published 2009 in Nature

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 μ constant region (Cμ) exons, which are the first of several sets of CH exons (‘CH genes’) within a CH locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cμ and replaces it with a downstream CH gene. An intronic enhancer (iEμ) between the variable region exons and Cμ promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3′ regulatory region (Igh3′RR) lies downstream of the CH locus and modulates CSR by long-range transcriptional enhancement of CH genes. Transgenic mice bearing iEμ 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 iEμ 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.

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