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Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia

Nature volume 423, pages 452–456 (2003)Cite this article

Abstract

Acute lymphoblastic leukaemia (ALL) is the commonest form of childhood malignancy, and most cases arise from B-cell clones arrested at the pre-B-cell stage of differentiation1,2. The molecular events that arrest pre-B-cell differentiation in the leukaemic pre-B cells have not been well characterized. Here we show that the differentiation regulator SLP-65 (an adaptor protein also called BLNK or BASH3,4,5,6) inhibits pre-B-cell leukaemia in mice. Reconstitution of SLP-65 expression in a SLP-65-/- pre-B-cell line led to enhanced differentiation in vitro and prevented the development of pre-B-cell leukaemia in immune-deficient mice. Tyrosine 96 of SLP-65 was required for this activity. The murine SLP-65-/- pre-B-cell leukaemia resembles human childhood pre-B ALL. Indeed, 16 of the 34 childhood pre-B ALL samples that were tested showed a complete loss or drastic reduction of SLP-65 expression. This loss is probably due to the incorporation of alternative exons into SLP-65 transcripts, leading to premature stop codons. Thus, the somatic loss of SLP-65 and the accompanying block in pre-B-cell differentiation might be one of the primary causes of childhood pre-B ALL.

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Figure 1: The Btk binding site is essential for the tumour suppressor activity of SLP-65.
Figure 2: Absence of SLP-65 expression in samples derived from pre-B ALL patients.
Figure 3: SLP-65 expression in CD19-purified lymphoblasts from patients with pre-B ALL.

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Acknowledgements

We thank E. Bergsträsser (Zürich), U. zur Stadt (Hamburg), J. Harbott (Giessen) and O. G. Ottmann (Frankfurt) for pre-B ALL samples; W.-D. Ludwig (Berlin) and J. Harbott (Giessen) for immunophenotyping and molecular genetic studies of the patients from Freiburg and Hanover; P. Nielsen for reading the manuscript and H. Mossmann for help in the mouse experiments; and C. Eschbach and U. Stauffer for technical support. Financial support for these experiments was provided by the Deutsche Forschungs Gemeinschaft and the Leibniz programme to M.R.

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  1. Lukas Bossaller, Karina Portugal, Bettina Storch and Charlotte M. Niemeyer: These authors contributed equally to this work

Authors and Affiliations

  1. Biologie III, University of Freiburg and Max Planck Institute for Immunobiology, D-79108, Freiburg, Germany

    Hassan Jumaa, Lukas Bossaller, Karina Portugal, Bettina Storch, Michael Lotz, Alexandra Flemming & Michael Reth

  2. Pediatric Hematology and Oncology, Children's Hospital, Medical School of Hanover, D-30625, Hanover, Germany

    Martin Schrappe

  3. Department of Clinical Microbiology, University of Kuopio, PO Box 1627

    Ville Postila & Jukka Pelkonen

  4. Department of Clinical Microbiology, Kuopio University Hospital, PO Box 1777, FIN-70211, Kuopio, Finland

    Ville Postila & Jukka Pelkonen

  5. Department of Pediatrics, Kuopio University Hospital, PO Box 1777, FIN-70211, Kuopio, Finland

    Pekka Riikonen

  6. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Freiburg University Hospital, D-79106, Freiburg, Germany

    Charlotte M. Niemeyer

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Correspondence to Hassan Jumaa or Michael Reth.

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Jumaa, H., Bossaller, L., Portugal, K. et al. Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia. Nature 423, 452–456 (2003). https://doi.org/10.1038/nature01608

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