The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation.
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.
Feinberg
Mark W
MW
Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. mfeinberg@rics.bwh.harvard.edu
Wara
Akm Khyrul
AK
Cao
Zhuoxiao
Z
Lebedeva
Maria A
MA
Rosenbauer
Frank
F
Iwasaki
Hiromi
H
Hirai
Hideyo
H
Katz
Jonathan P
JP
Haspel
Richard L
RL
Gray
Susan
S
Akashi
Koichi
K
Segre
Julie
J
Kaestner
Klaus H
KH
Tenen
Daniel G
DG
Jain
Mukesh K
MK
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D004247:DNA / Q000378:metabolism; D006413:Hematopoietic System / Q000166:cytology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D051379:Mice; D009000:Monocytes / Q000166:cytology*; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000172:deficiency; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000172:deficiency; D015533:Transcriptional Activation / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D004247:DNA; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D018950:Lipopolysaccharide Receptors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat