Letter | Published:

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

Nature volume 462, pages 803807 (10 December 2009) | Download Citation

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)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)2,3,4. 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 span several hundred kilobases (kb)5,6. In mature B cells, CSR deletes Cμ and replaces it with a downstream CH gene6. An intronic enhancer (iEμ) between the variable region exons and Cμ promotes V(D)J recombination in developing B cells7. Furthermore, the Igh 3′ regulatory region (Igh3′RR) lies downstream of the CH locus and modulates CSR by long-range transcriptional enhancement of CH genes8,9,10. 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 expression11,12,13,14,15,16. However, in many B-cell lymphomas, Ighc-myc translocations delete iEμ 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 Ighc-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 Ighc-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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Acknowledgements

We thank L. G. Jiang for help with cloning translocation breakpoints. This work was supported by National Institutes of Health (NIH) grant CA92625 and the Leukemia and Lymphoma Society of America (LLS) SCORE grant to F.W.A. M.G. was a Special Fellow of the LLS and C.T.Y. was supported by an NCI training grant. M.G. and C.T.Y. were also supported by the de Villiers International Achievement Award of the LLS to F.W.A. E.P. was a Fellow of the Fondation pour la Recherche Médicale. F.W.A. is an Investigator of the Howard Hughes Medical Institute.

Author Contributions F.W.A. and M.G. planned studies and interpreted data. M.G. performed experiments, with technical help from J.M.B. C.T.Y generated CXP mice. E.P. and M.C. generated Igh3′RR-deleted mice and helped interpret data. F.W.A. and M.G. wrote the paper.

Author information

Affiliations

  1. Howard Hughes Medical Institute,

    • Monica Gostissa
    • , Catherine T. Yan
    • , Julia M. Bianco
    •  & Frederick W. Alt
  2. The Children’s Hospital,

    • Monica Gostissa
    • , Catherine T. Yan
    • , Julia M. Bianco
    •  & Frederick W. Alt
  3. Immune Disease Institute,

    • Monica Gostissa
    • , Catherine T. Yan
    • , Julia M. Bianco
    •  & Frederick W. Alt
  4. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Monica Gostissa
    • , Catherine T. Yan
    • , Julia M. Bianco
    •  & Frederick W. Alt
  5. Centre National de la Recherche Scientifique; Université de Limoges, UMR 6101, Faculté de Médecine, Limoges France

    • Michel Cogné
    •  & Eric Pinaud

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Corresponding author

Correspondence to Frederick W. Alt.

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https://doi.org/10.1038/nature08633

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