Article
- The EMBO Journal (2007) 26, 4138 - 4148
- doi:10.1038/sj.emboj.7601824
Published online: 30 August 2007
Subject Categories:
The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation
Mark W Feinberg1, Akm Khyrul Wara1, Zhuoxiao Cao1, Maria A Lebedeva1, Frank Rosenbauer2, Hiromi Iwasaki3, Hideyo Hirai2, Jonathan P Katz4, Richard L Haspel5, Susan Gray1, Koichi Akashi3, Julie Segre6, Klaus H Kaestner4, Daniel G Tenen2 and Mukesh K Jain7
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Institutes of Medicine, Boston, MA, USA
- The Department of Cancer and Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- Cardiovascular Division, Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA
Correspondence to:
Mark W Feinberg, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. Tel.: +1 617 525 4381; Fax: +1 617 525 4380; E-mail: mfeinberg@rics.bwh.harvard.edu
Mukesh K Jain, Cardiovascular Division, Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Room 4537, Cleveland, OH 44106, USA. Tel.: +1 216 368 3607; Fax: +1 216 368 0556; E-mail: Mukesh.Jain2@case.edu
Received 19 February 2007; Accepted 19 July 2007
Abstract
Monocyte differentiation involves the participation of lineage-restricted transcription factors, although the mechanisms by which this process occurs are incompletely defined. Within the hematopoietic system, members of the Kruppel-like family of factors (KLFs) play essential roles in erythrocyte and T lymphocyte development. Here we show that KLF4/GKLF is expressed in a monocyte-restricted and stage-specific pattern during myelopoiesis and functions to promote monocyte differentiation. Overexpression of KLF4 in HL-60 cells confers the characteristics of mature monocytes. Conversely, KLF4 knockdown blocked phorbol ester-induced monocyte differentiation. Forced expression of KLF4 in primary common myeloid progenitors (CMPs) or hematopoietic stem cells (HSCs) induced exclusive monocyte differentiation in clonogenic assays, whereas KLF4 deficiency inhibited monocyte but increased granulocyte differentiation. Mechanistic studies demonstrate that KLF4 is a target gene of PU.1. Consistently, KLF4 can rescue PU.1–/– fetal liver cells along the monocytic lineage and can activate the monocytic-specific CD14 promoter. Thus, KLF4 is a critical regulator in the transcriptional network controlling monocyte differentiation.
Keywords:
- hematopoietic progenitors,
- Kruppels,
- leukemia,
- monocyte differentiation,
- PU.1
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