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* Divisions of Immunology and Hematopoiesis,
Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center,
Stem Cell Program, Institute of Cell Engineering, and
Hematology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
Several members of the Kruppel-like factor (KLF) family of transcription factors play important roles in differentiation, survival, and trafficking of blood and immune cell types. We demonstrate in this study that hematopoietic cells from KLF4–/– fetal livers (FL) contained normal numbers of functional hematopoietic progenitor cells, were radioprotective, and performed as well as KLF4+/+ cells in competitive repopulation assays. However, hematopoietic "KLF4–/– chimeras" generated by transplantation of KLF4–/– fetal livers cells into lethally irradiated wild-type mice completely lacked circulating inflammatory (CD115+Gr1+) monocytes, and had reduced numbers of resident (CD115+Gr1–) monocytes. Although the numbers and function of peritoneal macrophages were normal in KLF4–/– chimeras, bone marrow monocytic cells from KLF4–/– chimeras expressed lower levels of key trafficking molecules and were more apoptotic. Thus, our in vivo loss-of-function studies demonstrate that KLF4, previously shown to mediate proinflammatory signaling in human macrophages in vitro, is essential for differentiation of mouse inflammatory monocytes, and is involved in the differentiation of resident monocytes. In addition, inducible expression of KLF4 in the HL60 human acute myeloid leukemia cell line stimulated monocytic differentiation and enhanced 12-O-tetradecanoylphorbol 13-acetate induced macrophage differentiation, but blocked all-trans-retinoic acid induced granulocytic differentiation of HL60 cells. The inflammation-selective effects of loss-of-KLF4 and the gain-of-KLF4-induced monocytic differentiation in HL60 cells identify KLF4 as a key regulator of monocytic differentiation and a potential target for translational immune modulation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported in part by a Fellow Award from the National Foundation for Cancer Research and National Institutes of Health Grant CA070970.
2 Address correspondence and reprint requests to Dr. Curt I. Civin, BB CRB 1 Room 2M44, 1650 Orleans Street, Baltimore, MD 21231. E-mail address: civincu{at}jhmi.edu
3 Abbreviations used in this paper: KLF, Kruppel-like factor; HSPC, hematopoietic stem-progenitor cell; BM, bone marrow; ES, embryonic stem; HSC, hemopoietic stem cell; HPC, hematopoietic progenitor; FL, fetal liver; wt, wild type; PE, peritoneal exudate; TPA, 12-O-tetradecanoylphorbol 13-acetate; RA, retinoic acid; ER, estrogen receptor; 4HT, 4-hydroxy-tamoxifen; CFC, colony-forming cell; SCF, stem cell factor; M-CSF, monocyte-CSF; PI, propidium iodide; qRT-PCR, quantitative-RT-PCR.
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