Role of the reprogramming factor KLF4 in blood formation

Abstract

Krüppel-like factor 4 is a zinc finger protein with dual functions that can act as a transcriptional activator and repressor of genes involved in cell proliferation, differentiation, and apoptosis. Although most studies have focused on terminally differentiated epithelial cells, evidence suggests that Krüppel-like factor 4 regulates the development and function of the myeloid and lymphoid blood lineages. The ability of Krüppel-like factor 4 to dedifferentiate from somatic cells into pluripotent stem cells in cooperation with other reprogramming factors suggests its potential function in the preservation of tissue-specific stem cells. Additionally, emerging interest in the redifferentiation of induced pluripotent stem cells into blood cells to correct hematologic deficiencies and malignancies warrants further studies on the role of Krüppel-like factor 4 in steady-state blood formation.

Conditional knockout mice demonstrate function of Klf5 as a myeloid transcription factor

“…5,23 KLF4 controls monocyte lineage fate and is also a target of gene silencing in AML. 3 Other KLFs also have roles in hematopoiesis and leukemia; for example, KLF1 is a master regulator of erythropoiesis and variation at the KLF1 locus underlies a large spectrum of red blood cell disorders.…”

Novel tumor-suppressor function of KLF4 in pediatric T-cell acute lymphoblastic leukemia

“…The Krüppel-like factor 4 (KLF4) protein contains both activating and repressing domains and regulates gene expression by different mechanisms: direct DNA binding to unmethylated and methylated promoters and recruitment of co-activators or co-repressors, protein-to-protein interactions, organization of higher chromatin structures, and regulation of the epigenome (13). This tissue-dependent dual function as activators and repressors of gene expression might drive KLF4 to function as a tumor suppressor in the gastrointestinal tract and as an oncogene in breast cancer (14, 15).…”

“…This tissue-dependent dual function as activators and repressors of gene expression might drive KLF4 to function as a tumor suppressor in the gastrointestinal tract and as an oncogene in breast cancer (14, 15). Aside from solid tumors, the role of KLF4 has not been well defined in hematological malignancies, although KLF4 is known to regulate blood formation, homeostatic proliferation of naïve T cells, and monocytic differentiation (13, 16–18). Previous reports of gene expression and mutations have positioned KLF4 as a potential negative regulator of leukemogenesis.…”

Potential therapeutic targets in Nrf2-dependent protection against neonatal respiratory distress disease predicted by cDNA microarray analysis and bioinformatics tools

“…Nrf1, similar to Nrf2, is known to regulate ARE-bearing antioxidants but it also modulates inflammatory responses [30]. Klf4 (Krüppel-like factor 4) is a pluripotent transcription factor known to be involved in carcinogenesis or anti-carcinogenesis by modulating various genes (e.g., p21, cyclins, Bcl2) in cell cycle and survival [31]. It corresponds to the pathway analysis (http://www.ingenuity.com/products/ipa) in which these genes were highly linked to the T cell development and T cell receptor signaling (Figure 1-B) with interleukin 7 and TCF3 as predicted upstream regulators.…”