Access

Letters to Nature

Nature 423, 452-456 (22 May 2003) | doi:10.1038/nature01608; Received 30 January 2003; Accepted 28 March 2003

Open Innovation Challenges

naturejobs

More science jobs
Post a job for free

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

Hassan Jumaa1, Lukas Bossaller1,2, Karina Portugal1,2, Bettina Storch1,2, Michael Lotz1, Alexandra Flemming1, Martin Schrappe3, Ville Postila4, Pekka Riikonen5, Jukka Pelkonen4, Charlotte M. Niemeyer6 & Michael Reth1

  1. Biologie III, University of Freiburg and Max Planck Institute for Immunobiology, D-79108 Freiburg, Germany
  2. Pediatric Hematology and Oncology, Children's Hospital, Medical School of Hanover, D-30625 Hanover, Germany
  3. Department of Clinical Microbiology, University of Kuopio PO Box 1627, and Department of Clinical Microbiology, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland
  4. Department of Pediatrics, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland
  5. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Freiburg University Hospital, D-79106 Freiburg, Germany
  6. These authors contributed equally to this work

Correspondence to: Hassan Jumaa1Michael Reth1 Correspondence and requests for materials should be addressed to M.R. (Email: reth@immunbio.mpg.de) or H.J. (Email: jumaa@immunbio.mpg.de).

Top

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.