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

Monocyte differentiation involves the participation of line-age-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.