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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1396-1403.
Prepublished online as a Blood First Edition Paper on October 30, 2007; DOI 10.1182/blood-2007-08-110106.
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Submitted August 29, 2007
Accepted October 22, 2007
Interferon regulatory factor 4 & 8 induce the expression of Ikaros and Aiolos to downregulate pre-BCR and promote cell cycle withdrawal in pre-B cell development
Shibin Ma, Simanta Pathak, Long Trinh, and Runqing Lu*
Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE, United States
* Corresponding author; email: rlu{at}unmc.edu.
Pre-B lymphocytes consist of two distinct cell populations: large pre-B and small pre-B. The large pre-B cells are newly generated pre-B cells that express pre-B cell receptor (pre-BCR) on the surface and are highly proliferative; small pre-B cells are derived from large pre-B cells that have downregulated pre-BCR and withdrawn from cell cycle. The molecular events that mediate the transition from cycling pre-B to small, resting pre-B have not been fully elucidated. Here, we show that interferon regulatory factor 4 & 8 (IRF4,8) suppress surrogate light chain expression and downregulate pre-BCR in pre-B cells. Our studies further reveal that IRF4,8 induce the expression of Ikaros and Aiolos in pre-B cells, and reconstitution of expression of either one is sufficient to suppress surrogate light chain expression and downregulate pre-BCR in pre-B cells lacking IRF4,8. Interestingly, our results also indicate that pre-B cells undergo growth inhibition and cell cycle arrest in the presence of IRF4,8. Moreover, we provide evidence that Ikaros and Aiolos are indispensable for the downregulation of pre-BCR and the cell cycle withdrawal mediated by IRF4,8. Thus, IRF4,8 orchestrate the transition from large pre-B to small pre-B cells by inducing the expression of Ikaros and Aiolos.
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