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Acute Leukemias

Pre-B-cell leukemias in Btk/Slp65-deficient mice arise independently of ongoing V(D)J recombination activity

Leukemia volume 25, pages 48–56 (2011)Cite this article

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Abstract

The adapter protein Slp65 and Bruton's tyrosine kinase (Btk) are key components of the precursor-B (pre-B) cell receptor (pre-BCR) signaling pathway. Slp65-deficient mice spontaneously develop pre-B-cell leukemia, expressing high levels of the pre-BCR on their cell surface. As leukemic Slp65-deficient pre-B cells express the recombination activating genes (Rag)1 and Rag2, and manifest ongoing immunoglobulin (Ig) light-chain rearrangement, it has been hypothesized that deregulated recombinase activity contributes to malignant transformation. In this report, we investigated whether Rag-induced DNA damage is involved in oncogenic transformation of Slp65-deficient B cells. We employed Btk/Slp65 double-deficient mice carrying an autoreactive 3–83μδ BCR transgene. When developing B cells in their bone marrow express this BCR, the V(D)J recombination machinery will be activated, allowing for secondary Ig light-chain gene rearrangements to occur. This phenomenon, called receptor editing, will rescue autoreactive B cells from apoptosis. We observed that 3-83μδ transgenic Btk/Slp65 double-deficient mice developed B-cell leukemias expressing both the 3-83μδ BCR and the pre-BCR components λ5/VpreB. Importantly, such leukemias were found at similar frequencies in mice concomitantly deficient for Rag1 or the non-homologous end-joining factor DNA-PKcs. We therefore conclude that malignant transformation of Btk/Slp65 double-deficient pre-B cells is independent of deregulated V(D)J recombination activity.

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Acknowledgements

We thank H Jumaa (Freiburg, Germany) and D Nemazee (The Scripps Research Institute, La Jolla, CA, USA) for providing us with respectively the Slp65-deficient and 3-83μδ Tg mice. We also thank S Middendorp, J Essers and H Diepstraten (Erasmus MC) for their assistance. This work was supported by the Netherlands Organization for Scientific Research (NWO) and the Dutch Cancer Society (KWF).

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Authors and Affiliations

  1. Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands

    V B T Ta, A B de Haan, M J W de Bruijn & R W Hendriks

  2. Department of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands

    V B T Ta, G M Dingjan & R W Hendriks

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Correspondence to R W Hendriks.

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Ta, V., de Haan, A., de Bruijn, M. et al. Pre-B-cell leukemias in Btk/Slp65-deficient mice arise independently of ongoing V(D)J recombination activity. Leukemia 25, 48–56 (2011). https://doi.org/10.1038/leu.2010.246

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