| Dysregulated PI3K activity in B cells has been implicated in many human diseases. Gene-targeting studies, including deletion of the BCR co-receptor CD19, have revealed that members of the PI3K pathway are important for normal B cell function. Given the multiple isoforms, downstream targets, and activators of PI3K, it is difficult to understand precisely how this pathway affects B cell function and disease progression. The global PI3K antagonist, PTEN is a tumor suppressor in multiple human cancers. In B cells, the 5 ' phosphatase SHIP regulates PI3K in a receptor-restricted manner. Surprisingly, there is little evidence to implicate SHIP as a tumor suppressor. Here, to ask about the importance of PI3K regulation in B cells, we have generated bPten-/- and bShip -/- mice that lack either PTEN or SHIP specifically in the B cell compartment. Our studies reveal that lack of either PI3K antagonist leads to specific alterations in B cell fate and immune responses. Restoration of CD19 function in B cells lacking PTEN supports PI3K activation as the important mechanism of augmentation by this B cell coreceptor. Additionally, whereas previous reports demonstrate that T cell-specific PTEN deletion in mice causes lymphoma, PTEN loss does not cause tumor formation in B cells. However, lymphoma progression in mice lacking both SHIP and PTEN in B cells provides the first direct evidence that SHIP can act as a tumor suppressor. |
