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


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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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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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).

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