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

H Jumaa, L Bossaller, K Portugal, B Storch, M Lotz… - Nature, 2003 - nature.com
H Jumaa, L Bossaller, K Portugal, B Storch, M Lotz, A Flemming, M Schrappe, V Postila…
Nature, 2003nature.com
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,. 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,,,) 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 …
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,. 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,,,) 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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