Rampant proliferation of pre–B cells in leukemia can be caused by overly active proto-oncogenes such as c-Myc. Wossning et al. (page 2829) now discover that this c-Myc surplus is driven by a tyrosine kinase called Syk. But even with lots of c-Myc, pre–B cells still need Syk to cycle.
B cell proliferation and differentiation must be tightly controlled to avoid the release of immature, nonfunctional cells into the circulation. The proliferation is driven by the pre–B cell receptor (pre-BCR), which activates Syk. Syk's role in proliferation is murky: it is overexpressed in some types of lymphoma and leukemia cells, yet it activates a known tumor suppressor and is down-regulated in certain malignant cancers.
To sort through this confusion, Wossning et al. overexpressed Syk in pre–B cells, which transformed the cells into an overproliferative, undifferentiated state. A Syk-specific inhibitor reversed this phenotype. The team thus concludes that Syk is a proto-oncogene rather than tumor suppressor, at least in this cell type.
The group also found that Syk promoted c-Myc expression. The addition of more c-Myc was all that was needed to transform pre–B cells, yet this transformation was reversed by Syk inhibition. Furthermore, c-Myc expression did not transform pre–B cells that lacked the pre-BCR. Together, these results indicate that Syk must be turning on other necessary proliferative or survival signals—perhaps Bcl-2 family members—in addition to c-Myc.
The finding that transformation resulting from either too much Syk or too much c-Myc can both be blocked with a Syk inhibitor suggests that a variety of B cell proliferative disorders might respond to this type of treatment.