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Molecular and Cellular Biology, December 2006, p. 9364-9376, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.00839-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Essential Role of Phospholipase C{gamma}2 in Early B-Cell Development and Myc-Mediated Lymphomagenesis{triangledown}

Renren Wen,1,{dagger}* Yuhong Chen,1,{dagger} Li Bai,1,2 Guoping Fu,1 James Schuman,1 Xuezhi Dai,1,3 Hu Zeng,1,3 Chunying Yang,4 Robert P. Stephan,5 John L. Cleveland,4 and Demin Wang1,6*

Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin 53226,1 Dali University, Dali, Yunnan, People's Republic of China,2 State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University, Nanjing 210093, People's Republic of China,3 Department of Biochemistry, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105,4 Division of Developmental and Clinical Immunology, University of Alabama, Birmingham, Alabama 35294,5 Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 532266

Received 11 May 2006/ Returned for modification 7 June 2006/ Accepted 21 September 2006

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–/– Eµ-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 Eµ-Myc transgenics. Furthermore, lymphomas from PLC{gamma}2–/– Eµ-Myc transgenic mice exhibited a loss of p27Kip1 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.

* Corresponding author. Mailing address: Blood Research Institute, 8727 Watertown Plank Road, Milwaukee, WI 53226. Phone: (414) 937-3874. Fax: (414) 937-6284. E-mail for Renren Wen: renren.wen{at}bcw.edu. E-mail for Demin Wang: demin.wang{at}bcw.edu.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, December 2006, p. 9364-9376, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.00839-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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