Elsevier

Blood Cells, Molecules, and Diseases

Volume 39, Issue 3, November–December 2007, Pages 340-343
Blood Cells, Molecules, and Diseases

C/EBPα induces PU.1 and interacts with AP-1 and NF-κB to regulate myeloid development

https://doi.org/10.1016/j.bcmd.2007.06.010Get rights and content

Abstract

C/EBPα and PU.1 are key regulators of early myeloid development. Mice lacking C/EBPα or PU.1 have reduced granulocytes and monocytes. Consistent with a model in which induction of PU.1 by C/EBPα contributes to monocyte lineage specification, mice with reduced PU.1 have diminished monocytes but retain granulocytes, C/EBPα directly activates PU.1 gene transcription, and exogenous C/EBPα increases monocytic lineage commitment from bipotential myeloid progenitors. In addition to C/EBPα, AP-1 proteins also have the capacity to induce monocytic maturation. C/EBPα:c-Jun or C/EBPα:c-Fos leucine zipper heterodimers induce monopoiesis more potently than C/EBPα or c-Jun homodimers or c-Fos:c-Jun heterodimers. C/EBPs and NF-κB cooperatively regulate numerous genes during the inflammatory response. The C/EBPα basic region interacts with NF-κB p50, but not p65, to induce bcl-2, and this interaction may be relevant to myeloid cell survival and development.

Introduction

The focus of this report is our laboratory's work on the role of C/EBPα as a regulator of myeloid (granulocyte versus monocyte) lineage commitment. A comprehensive overview of the regulation of myeloid development may be found in two published reviews [1], [2].

Section snippets

Myeloid defects in mice with reduced or absent C/EBPα or PU.1

C/EBPα(−/−) newborn mice lack neutrophils and have reduced hepatic monocytes, and their marrow CFU-M numbers are decreased 2-fold [3]. Deletion of C/EBPα in the marrow of adult mice inhibits the common myeloid progenitor (CMP) to granulocyte-monocyte progenitor (GMP) transition [4]. Consistent with these findings, analysis of an independently derived C/EBPα(−/−) line demonstrates reduced CFU-GM, neutrophils, and monocyte/macrophages [5]. A dominant-inhibitory C/EBP, KRAB-C/EBPα-ER, inhibits

C/EBPα induces PU.1 gene transcription

C/EBPα-ER rapidly induces endogenous PU.1 mRNA in Ba/F3 or 32Dcl3 hematopoietic cell lines even in the presence of cycloheximide, but C/EBPα(L12V)-ER, which cannot heterodimerize or bind DNA due to mutation of the first two leucines of the leucine zipper (LZ) to valine, does not induce PU.1 mRNA [15], [16]. C/EBPα binds the murine PU.1 promoter in a chromosomal immunoprecipitation (ChIP) assay and binds the sequence TAGCGCAAG located at − 68 in the murine PU.1 promoter and conserved in the human

C/EBPα induces monocyte lineage commitment in cooperation with PU.1

To complement gene knockout loss-of-function studies, we have assessed the ability of exogenous C/EBPα to affect myeloid lineage commitment from murine marrow progenitors. As C/EBPα potently inhibits G1 to S cell cycle progression in myeloid cells via interaction with E2F1 and likely other mechanisms [18], [19], [20], [21], we developed an assay that minimizes biases due to lineage-specific cell cycle inhibition. One feature of our approach is use of C/EBPα-ER fusion proteins that remain

C/EBPα zippers with AP-1 proteins to favor monopoiesis

The initial suggestion that AP-1 proteins favor monocytic development comes from the finding that c-Jun or c-Fos can induce monocytic differentiation when expressed in myeloid cell lines and from the observation that phorbol esters rapidly induce AP-1 proteins and direct myeloid cell maturation to monocytes [27], [28], [29]. MafB can zipper with c-Fos, and c-Maf zippers with c-Jun, JunB or c-Fos [30]. MafB is expressed predominantly in monocytic cells within hematopoiesis, and MafB or c-Maf

C/EBPα interacts with NF-κB to regulate inflammation, survival and potentially myelopoiesis

C/EBPs and NF-κB cooperate to induce the IL-6, IL-8, G-CSF, serum amyloid, ICAM-1, superoxide dismutase and Mediterranean fever promoters during the inflammatory response [36], [37], [38], [39], [40]. The bZIP domain of C/EBPα or C/EBPβ interacts with NF-κB p50 or p65 [41], [42]. C/EBPα or C/EBPβ cooperates specifically with NF-κB p50 to activate the bcl-2 P2 promoter, leading to inhibition of apoptosis in myeloid or lymphoid cells. Endogenous C/EBPα preferentially interacts with endogenous

Summary and future directions

Onset of C/EBPα expression in multipotent stem/progenitors cells, such as the lymphoid-myeloid progenitor (LMMP) or CMP, may direct these cells to the GMP state, initiating myeloid development (Fig. 1). In this model, induction of PU.1 in cooperation with AP-1 and monocyte-specific cytokine signals directs monopoiesis, and C/EBPα and reduced PU.1 cooperate with other transcription factors to direct granulopoiesis. Many key questions remain. It will be of interest to identify monocytic genes

Acknowledgments

I thank the members of my laboratory and participants at the Myeloid Workshop for useful discussions. This work is supported by NIH grants HL082948 and CA098805. This paper is a summary of a presentation at the Seventh International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukemia, Annapolis, Maryland, May 13–16, 2007, sponsored by The Leukemia and Lymphoma Society.

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