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

Jumaa, Hassan; Bossaller, Lukas; Portugal, Karina; Storch, Bettina; Lotz, Michael; Flemming, Alexandra; Schrappe, Martin; Postila, Ville; Riikonen, Pekka; Pelkonen, Jukka; Niemeyer, Charlotte M.; Reth, Michael

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

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Jumaa, Hassan
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Bossaller, Lukas
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Portugal, Karina
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Storch, Bettina
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Lotz, Michael
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Flemming, Alexandra
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Reth, Michael
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Jumaa, H., Bossaller, L., Portugal, K., Storch, B., Lotz, M., Flemming, A., et al. (2003). Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia. Nature, 423(6938), 452-456.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-9534-7

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 differentiation^1,2. 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 BASH^3-6) 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.