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 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.
Wen
Renren
R
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA. renren.wen@bcw.edu
Chen
Yuhong
Y
Bai
Li
L
Fu
Guoping
G
Schuman
James
J
Dai
Xuezhi
X
Zeng
Hu
H
Yang
Chunying
C
Stephan
Robert P
RP
Cleveland
John L
JL
Wang
Demin
D
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008223:Lymphoma / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051966:Phospholipase C gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054420:Pre-B Cell Receptors; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology
D007527:Isoenzymes; C489427:MYC protein, human; D008562:Membrane Glycoproteins; D054420:Pre-B Cell Receptors; D016271:Proto-Oncogene Proteins c-myc; D011947:Receptors, Antigen, B-Cell; D051966:Phospholipase C gamma