Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 26, Issue 24, Pages 9364-9376Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00839-06
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Funding
- NCI NIH HHS [R01 CA76379, P30 CA021765, CA-21765, R01 CA076379] Funding Source: Medline
- NHLBI NIH HHS [R01 HL073284] Funding Source: Medline
- NIAID NIH HHS [R01 AI52327, R01 AI052327] Funding Source: Medline
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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.
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