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

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.

SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells

“…Reconstitution of SLP65 expression in SLP65-deficient leukemia and lymphoma cells results in downregulation of RAG1/2 expression and prevents both de novo V H -DJ H rearrangements and secondary V H replacement. We conclude that iterative V H gene rearrangement represents a frequent feature in B-lymphoid malignancy, which can be attributed to SLP65 deficiency in many cases.Oncogene ( Recent work demonstrated that deficiency of SLP65 (SH2 domain-containing lymphocyte protein of 65 kDa) is a frequent feature in acute lymphoblastic leukemia cells (Jumaa et al, 2003;Klein et al, 2004). Although a recent report questioned these findings (Imai et al, 2004), this study shows that defective SLP65 expression is not only frequent in human pre-B-lymphoblastic leukemia but also occurs in a fraction of mature B-cell lymphoma cases.…”

“…Oncogene ( Recent work demonstrated that deficiency of SLP65 (SH2 domain-containing lymphocyte protein of 65 kDa) is a frequent feature in acute lymphoblastic leukemia cells (Jumaa et al, 2003;Klein et al, 2004). Although a recent report questioned these findings (Imai et al, 2004), this study shows that defective SLP65 expression is not only frequent in human pre-B-lymphoblastic leukemia but also occurs in a fraction of mature B-cell lymphoma cases.…”

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

“…Aberrant processing of mRNAs in tumor cells has been described for the MDM2, RasGRP4, SLP-65, TLE1, TLE4, MTA1 and CD44 genes and is emerging as an important characteristic of tumor cells (Bartel et al, 2002;Kumar et al, 2002;Reuther et al, 2002;Yang et al, 2002;Jumaa et al, 2003;Venables, 2004;Watermann et al, 2006) and is observed in other diseases, such as myotonic dystrophy (Charlet-B et al, 2002). In aberrant splicing, portions of exons, portions of introns or both are retained within transcripts that fail to be purged by the cellular pathways designed to scavenge abnormal mRNAs, such as nonsense-mediated decay (Culbertson, 1999;Wilkinson and Shyu, 2002).…”

Btk and phospholipase Cγ2 can function independently during B cell development

“…Polymorphisms that reduce PLCc2 signaling may exacerbate B cell defects in XLA patients. Reduced BLNK expression has been documented in some human pre-B acute lymphoblastic leukemia samples [62]. Defining the pathway by which Btk mediates tumor suppression may thus reveal novel therapeutic approaches for pre-B malignancies.…”