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

Hassan Jumaa (), Lukas Bossaller, Karina Portugal, Bettina Storch, Michael Lotz, Alexandra Flemming, Martin Schrappe, Ville Postila, Pekka Riikonen, Jukka Pelkonen, Charlotte M. Niemeyer and Michael Reth ()
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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
Pekka Riikonen: Kuopio University Hospital
Jukka Pelkonen: University of Kuopio
Charlotte M. Niemeyer: Freiburg University Hospital
Michael Reth: Biologie III, University of Freiburg and Max Planck Institute for Immunobiology

Nature, 2003, vol. 423, issue 6938, 452-456

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01608

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