Essential role of phospholipase Cγ2 in early B-cell development and Myc-mediated lymphomagenesis

Phospholipase C gamma 2 (PLC gamma 2) is a critical signaling effector of the B-cell receptor (BCR). Here we show that PLC gamma 2 deficiency impedes early B-cell development, resulting in an increase of B220(+) CD43(+) BP-1(+) CD24hi pre-BCR+ large pre-B cells. PLC gamma 2 deficiency impairs pre-BCR-mediated functions, leading to enhanced interleukin-7 (IL-7) signaling and elevated levels of RAGs in the selected large pre-B cells. Consequently, PLC gamma 2 deficiency renders large pre-B cells susceptible to transformation, resulting in dramatic acceleration of Myc-induced lymphomagenesis. PLC gamma 2(-/-) E mu-Myc transgenic mice mainly develop lymphomas of B220(+) CD43(+) BP-1(+) CD24(hi) pre-BCR+ large pre-B-cell origin, which are uncommon in wild-type E mu-Myc transgenics. Furthermore, lymphomas from PLC gamma 2(-/-) E mu-Myc transgemic mice exhibited a loss of p27(Kip1) and often displayed alterations in Arf or p53. Thus, PLC gamma 2 plays an important role in pre-BCR-mediated early B-cell development, and its deficiency leads to markedly increased pools of the most at-risk large pre-B cells, which display hyperresponsiveness to IL-7 and express high levels of RAGs, making them prone to secondary mutations and Myc-induced malignancy.