The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation

Mark W. Feinberg, Akm Khyrul Wara, Zhuoxiao Cao, Maria A. Lebedeva, Frank Rosenbauer, Hiromi Iwasaki, Hideyo Hirai, Jonathan P. Katz, Richard L. Haspel, Susan Gray, Koichi Akashi, Julie Segre, Klaus H. Kaestner, Daniel G. Tenen, Mukesh K. Jain

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190 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4138-4148
Number of pages11
JournalEMBO Journal
Volume26
Issue number18
DOIs
Publication statusPublished - Sep 19 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Feinberg, M. W., Wara, A. K., Cao, Z., Lebedeva, M. A., Rosenbauer, F., Iwasaki, H., Hirai, H., Katz, J. P., Haspel, R. L., Gray, S., Akashi, K., Segre, J., Kaestner, K. H., Tenen, D. G., & Jain, M. K. (2007). The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO Journal, 26(18), 4138-4148. https://doi.org/10.1038/sj.emboj.7601824