Role of KLFs in myeloid development, renewal, and activation. (A) KLF4 and PU.1 are expressed in a stage-specific pattern during myelopoiesis (adapted with permission; see Feinberg et al⁶² ). (B-F) Overexpression of KLF4 in CMPs or HSCs promotes exclusive monocyte differentiation, whereas PU.1 promotes both monocytic and granulocytic differentiation (adapted with permission; see Feinberg et al⁶² ). (G) Schematic overview of KLFs in monocyte biology. KLF4 is a downstream target gene of PU.1 that promotes monocyte differentiation from hematopoietic stem cell progenitors. High expression levels of KLF4 and c-Myc enable differentiated monocytes/macrophages capable of self-renewal, an effect regulated by MafB and c-Maf and potentially mediated by their respective downstream targets, PU.1 and Ets1/2. Statins induce KLF2, which can repress genes involved in macrophage activation. KLF4 promotes the development of inflammatory monocytes (Ly-6C⁺, CD62L⁺, CCR2⁺) in blood and tissues and, to a lesser extent, resident macrophages in tissues (Ly6C⁻, CD62L⁻, CCR2⁻).