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 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.