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 (BL), often harbor translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH)1. The nature of elements that activate oncogenes within such translocations has been a longstanding question. Translocations within IgH involve DNA double strand breaks (DSBs) initiated either by the RAG1/2 endonuclease during V(D)J recombination or by activation induced cytidine deaminase (AID) during class switch recombination (CSR)2-4. 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 spans several hundred kilobases5,6. In mature B cells, CSR deletes Cμ and replaces it with a downstream CH gene6. An enhancer (iEμ) between the variable region exons and Cμ promotes V(D)J recombination in developing B cells7. In addition, the IgH 3’ regulatory region (IgH3’RR) lies downstream of the CH locus and modulates CSR by long-range transcriptional enhancement of CH genes8-10. Transgenic mice bearing iEμ or IgH3’RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating such elements can confer oncogenic c-myc expression11-16. However, in many B cell lymphomas, IgH/c-myc translocations delete iEμ and place c-myc up to 200kb upstream of the IgH3’RR1. We now 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. The IgH3’RR is dispensable for pro-B lymphomas with V(D)J recombination-initiated translocations, but 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 this regulatory region confers oncogenic activity via long-range and developmental stage-specific activation of translocated c-myc genes.