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SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells

Oncogene volume 25, pages 5180–5186 (2006)Cite this article

Abstract

Perpetual V(D)J recombinase activity involving multiple DNA double-strand break events in B-cell lineage leukemia and lymphoma cells may introduce secondary genetic aberrations leading towards malignant progression. Here, we investigated defective negative feedback signaling through the (pre-) B-cell receptor as a possible reason for deregulated V(D)J recombinase activity in B-cell malignancy. On studying 28 cases of pre-B-lymphoblastic leukemia and 27 B-cell lymphomas, expression of the (pre-) B-cell receptor-related linker molecule SLP65 (SH2 domain-containing lymphocyte protein of 65 kDa) was found to be defective in seven and five cases, respectively. SLP65 deficiency correlates with RAG1/2 expression and unremitting VH gene rearrangement activity. Reconstitution of SLP65 expression in SLP65-deficient leukemia and lymphoma cells results in downregulation of RAG1/2 expression and prevents both de novo VH–DJH rearrangements and secondary VH replacement. We conclude that iterative VH gene rearrangement represents a frequent feature in B-lymphoid malignancy, which can be attributed to SLP65 deficiency in many cases.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

DLBCL:

diffuse large B-cell lymphoma

IGH :

immunoglobulin heavy chain

RSS:

recombination signal sequence

SLP65:

SH2 domain-containing lymphocyte protein of 65 kDa

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Acknowledgements

We thank Stefanie Jauch and Peter Wurst for excellent technical assistance. NF is supported by a fellowship from the German José-Carreras-Leukemia Foundation, MM is supported by the Deutsche Forschungsgemeinschaft through the Emmy-Noether-Programm and through Grants MU1616/2-1 and MU1616/3-1 (to MM), the German José-Carreras-Leukemia-Foundation (grant to MM), the Ministry of Science and Research for North Rhine-Westphalia through the Stem Cell Network NRW (to MM) and the Deutsche Krebshilfe (through Grants 10-1643-Si1 to RS and ‘Molecular Mechanisms of Malignant Lymphoma’ to RS and MM).

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Authors and Affiliations

  1. Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

    M Sprangers, N Feldhahn, S Liedtke & M Müschen

  2. Max-Planck-Institute for Immunobiology, Freiburg, Germany

    H Jumaa

  3. Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany

    R Siebert

Authors
  1. M Sprangers
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  2. N Feldhahn
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  3. S Liedtke
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  4. H Jumaa
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  5. R Siebert
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  6. M Müschen
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Correspondence to M Müschen.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

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Sprangers, M., Feldhahn, N., Liedtke, S. et al. SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells. Oncogene 25, 5180–5186 (2006). https://doi.org/10.1038/sj.onc.1209520

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