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

Author

Listed:
  • Hassan Jumaa

    (Biologie III, University of Freiburg and Max Planck Institute for Immunobiology)

  • Lukas Bossaller

    (Biologie III, University of Freiburg and Max Planck Institute for Immunobiology)

  • Karina Portugal

    (Biologie III, University of Freiburg and Max Planck Institute for Immunobiology)

  • Bettina Storch

    (Biologie III, University of Freiburg and Max Planck Institute for Immunobiology)

  • Michael Lotz

    (Biologie III, University of Freiburg and Max Planck Institute for Immunobiology)

  • Alexandra Flemming

    (Biologie III, University of Freiburg and Max Planck Institute for Immunobiology)

  • Martin Schrappe

    (Children's Hospital, Medical School of Hanover)

  • Ville Postila

    (University of Kuopio
    Kuopio University Hospital)

  • Pekka Riikonen

    (Kuopio University Hospital)

  • Jukka Pelkonen

    (University of Kuopio
    Kuopio University Hospital)

  • Charlotte M. Niemeyer

    (Freiburg University Hospital)

  • Michael Reth

    (Biologie III, University of Freiburg and Max Planck Institute for Immunobiology)

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.

Suggested Citation

  • Hassan Jumaa & Lukas Bossaller & Karina Portugal & Bettina Storch & Michael Lotz & Alexandra Flemming & Martin Schrappe & Ville Postila & Pekka Riikonen & Jukka Pelkonen & Charlotte M. Niemeyer & Mich, 2003. "Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia," Nature, Nature, vol. 423(6938), pages 452-456, May.
    • Handle: RePEc:nat:nature:v:423:y:2003:i:6938:d:10.1038_nature01608
    DOI: 10.1038/nature01608
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