Essential role of phospholipase C gamma 2 in early B-cell development and Myc-mediated lymphomagenesis

Phospholipase Cgamma2 (PLCgamma2) is a critical signaling effector of the B-cell receptor (BCR). Here we show that PLCgamma2 deficiency impedes early B-cell development, resulting in an increase of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B cells. PLCgamma2 deficiency impairs pre-BCR-mediated fun...

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Bibliographic Details
Published in:Molecular and cellular biology 2006-12, Vol.26 (24), p.9364-9376
Main Authors: Wen, Renren, Chen, Yuhong, Bai, Li, Fu, Guoping, Schuman, James, Dai, Xuezhi, Zeng, Hu, Yang, Chunying, Stephan, Robert P, Cleveland, John L, Wang, Demin
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - cytology
B-Lymphocytes - enzymology
B-Lymphocytes - metabolism
Cell Differentiation - genetics
Isoenzymes - deficiency
Isoenzymes - genetics
Isoenzymes - physiology
Lymphoma - enzymology
Lymphoma - etiology
Lymphoma - metabolism
Lymphoma - pathology
Membrane Glycoproteins - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Phospholipase C gamma - deficiency
Phospholipase C gamma - genetics
Phospholipase C gamma - physiology
Pre-B Cell Receptors
Proto-Oncogene Proteins c-myc - physiology
Receptors, Antigen, B-Cell - physiology
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Summary:Phospholipase Cgamma2 (PLCgamma2) is a critical signaling effector of the B-cell receptor (BCR). Here we show that PLCgamma2 deficiency impedes early B-cell development, resulting in an increase of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B cells. PLCgamma2 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, PLCgamma2 deficiency renders large pre-B cells susceptible to transformation, resulting in dramatic acceleration of Myc-induced lymphomagenesis. PLCgamma2(-/-) Emu-Myc transgenic mice mainly develop lymphomas of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B-cell origin, which are uncommon in wild-type Emu-Myc transgenics. Furthermore, lymphomas from PLCgamma2(-/-) Emu-Myc transgenic mice exhibited a loss of p27Kip1 and often displayed alterations in Arf or p53. Thus, PLCgamma2 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.
ISSN:0270-7306
1098-5549
DOI:10.1128/MCB.00839-06