IRF8 regulates B-cell lineage specification, commitment, and differentiation
Open Access
- 15 November 2008
- journal article
- Published by American Society of Hematology in Blood
- Vol. 112 (10), 4028-4038
- https://doi.org/10.1182/blood-2008-01-129049
Abstract
PU.1, IKAROS, E2A, EBF, and PAX5 comprise a transcriptional network that orchestrates B-cell lineage specification, commitment, and differentiation. Here we identify interferon regulatory factor 8 (IRF8) as another component of this complex, and show that it also modulates lineage choice by hematopoietic stem cells (HSCs). IRF8 binds directly to an IRF8/Ets consensus sequence located in promoter regions of Sfpi1 and Ebf1, which encode PU.1 and EBF, respectively, and is associated with transcriptional repression of Sfpi1 and transcriptional activation of Ebf1. Bone marrows of IRF8 knockout mice (IRF8−/−) had significantly reduced numbers of pre-pro-B cells and increased numbers of myeloid cells. Although HSCs of IRF8−/− mice failed to differentiate to B220+ B-lineage cells in vitro, the defect could be rescued by transfecting HSCs with wild-type but not with a signaling-deficient IRF8 mutant. In contrast, overexpression of IRF8 in HSC-differentiated progenitor cells resulted in growth inhibition and apoptosis. We also found that IRF8 was expressed at higher levels in pre-pro-B cells than more mature B cells in wild-type mice. Together, these results indicate that IRF8 modulates lineage choice by HSCs and is part of the transcriptional network governing B-cell lineage specification, commitment, and differentiation.This publication has 61 references indexed in Scilit:
- Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre–B-cell receptor and promote cell-cycle withdrawal in pre–B-cell developmentBlood, 2008
- Association of the pre-B cell receptor (BCR) expression level with the quality of pre-BII cell differentiation reveals hierarchical pre-BCR functionMolecular Immunology, 2007
- ICSBP/IRF-8 differentially regulates antigen uptake during dendritic-cell development and affects antigen presentation to CD4+ T cellsBlood, 2006
- Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophagesBlood, 2005
- The pre-B-cell receptor: selector of fitting immunoglobulin heavy chains for the B-cell repertoireNature Reviews Immunology, 2005
- ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cellsBlood, 2003
- Activation of the Murine Interleukin-12 p40 Promoter by Functional Interactions between NFAT and ICSBPOnline Journal of Public Health Informatics, 2003
- Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1.Genes & Development, 1996
- Octamer Binding Factors and Their Coactivator Can Activate the Murine PU.1 (spi-1) PromoterOnline Journal of Public Health Informatics, 1996
- Requirement of Transcription Factor PU.1 in the Development of Multiple Hematopoietic LineagesScience, 1994