Adaptor proteins mostly function as flexible molecular scaffolds that mediate protein–protein and protein–lipid interactions in signalling pathways. Writing in Nature Immunology, Alexandra Flemming and colleagues propose that an adaptor protein that is expressed during B-cell development — the SLP65 protein — is a tumour suppressor that limits the proliferation of precursor B cells and promotes their differentiation into mature cells.

B cells develop in a stepwise manner, from progenitor B cells to precursor (pre-) B cells to mature cells. A key checkpoint in pre-B-cell development is the surface expression of a pre-B-cell receptor (pre-BCR), which is needed to signal the selection and proliferation of these cells. The cells then differentiate, lose the pre-BCR and express the BCR of mature cells. It was known that mice lacking the Slp65 adaptor have more pre-B cells and fewer mature B cells than normal. This hinted at a role for SLP65 in pre-B cells, and Flemming et al. set out to investigate this.

The authors first isolated pre-B cells from the bone marrow of wild-type and Slp65−/− mice, growing them for short periods in vitro in the presence of interleukin-7 (IL-7). They found that the mutant cells showed a greater proliferative capacity than wild-type cells, and that a larger proportion expressed the pre-BCR — indeed, the authors also show that Slp65 usually downregulates the surface expression of this receptor. As one function of the pre-BCR is to signal proliferation, could the mutant cells multiply without it? The authors crossed Slp65−/− mice with mice lacking part of the pre-BCR, and found that isolated bone-marrow-derived B cells proliferated slowly. So, the increased proliferation of Slp65−/− B cells requires the high surface expression of pre-BCRs.

Flemming et al. then cultured Slp65−/− pre-B cells for longer periods, and showed that a signalling pathway involving the mitogen-activated protein kinase ERK, which is required for proliferation, was active. In addition, withdrawing IL-7 led to differentiation, as with wild-type cells, but adding back Slp65 markedly enhanced differentiation.

A small but significant percentage of the Slp65−/− mice developed solid tumours, mostly close to the scapula, and splenomegaly; all these tumours consisted solely of pre-B cells expressing pre-BCRs. The authors propose that the increased proliferation of mutant pre-B cells seen in culture causes this increase in tumours. But they also suggest that, as the proportion of tumours is small, increased expression of pre-BCRs is not sufficient for tumorigenesis; secondary mutations are required, and are given greater opportunity to occur. Whether proliferating pre-B cells are prone to such mutations is a question for the future.