Loss of the B-cell-specific adaptor SLP-65 is associated with a type of acute lymphoblastic leukaemia.
Although adaptors are useful gadgets for connecting unrelated objects, all sorts of problems arise when they get damaged or lost. Adaptor molecules have an important role in immune regulation — directly influencing B-cell maturation and the development of tolerance — but as Jumaa et al. report in Nature, loss of the B-cell-specific adaptor SLP-65 is associated with a type of acute lymphoblastic leukaemia (ALL).
ALL is the most common form of childhood cancer and often arises from a block in the B-cell development programme that occurs as cells differentiate from precursor (pre-) B cells to mature cells. Mice lacking Slp-65 have more pre-B cells and fewer mature B cells than wild-type mice, and 5–10% develop pre-B-cell leukaemia. In vitro, Slp65-/- cells also have a greater proliferative capacity. These data indicate that SLP-65 might limit proliferation of pre-B cells and promote differentiation into mature cells. To test this, the authors introduced either Slp-65 or a Slp-65 mutant into a Slp65-/- pre-B cell line — only the wild-type Slp-65 was able to induce differentiation into mature B cells. Also, on injection into immune-deficient mice, the cells expressing mutant Slp-65, but not wild-type Slp-65, caused pre-B-cell leukaemia. So, as human pre-B ALL has a similar phenotype, might it also have a similar defect in SLP-65 expression?
The authors tested bone marrow from 34 pre-B ALL patients and found that 47% had a complete loss or pronounced reduction in SLP-65 expression. This confirms that human pre-B ALL resembles mouse Slp65-/--induced pre-B-cell leukaemia, but what is causing this decrease in SLP-65? Analysis using reverse transcriptase polymerase chain reaction revealed that SLP-65-deficient B cells express aberrant SLP-65 mRNA transcripts containing an additional sequence between exon 3 and 4 of SLP-65. Sequence analysis of this region of SLP-65 revealed two alternative exons containing premature stop codons that — if incorporated into SLP-65 mRNA by alternative splicing — interupt the SLP-65 open reading frame. These findings indicate that SLP-65 deficiency might be a primary cause of pre-B ALL and improve our understanding of the mechanisms that underlie this disease.
Emma Croager
References
Jumaa, H. et al. Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia. Nature423, 452–456 (2003) | Article | PubMed |
Flemming, A. et al. The adaptor protein SLP-65 acts as a tumour suppressor that limits pre-B cell expansion. Nature Immunol.4, 38–43 (2003) | Article | PubMed |
