Concise Review: Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4

Abstract

Pluripotent and tissue‐specific stem cells, such as blood‐forming stem cells, are maintained through a balance of quiescence, self‐renewal, and differentiation. Self‐renewal is a specialized cell division that generates daughter cells with the same features as the parental stem cell. Although many factors are involved in the regulation of self‐renewal, perhaps the most well‐known factors are members of the Krüppel‐like factor (KLF) family, especially KLF4, because of the landmark discovery that this protein is required to reprogram somatic cells into induced pluripotent stem cells. Because KLF4 regulates gene expression through transcriptional activation or repression via either DNA binding or protein‐to‐protein interactions, the outcome of KLF4‐mediated regulation largely depends on the cellular context, cell cycle regulation, chromatin structure, and the presence of oncogenic drivers. This study first summarizes the current understanding of the regulation of self‐renewal by KLF proteins in embryonic stem cells through a KLF circuitry and then delves into the potential function of KLF4 in normal hematopoietic stem cells and its emerging role in leukemia‐initiating cells from pediatric patients with T‐cell acute lymphoblastic leukemia via repression of the mitogen‐activated protein kinase 7 pathway. stem cells translational medicine 2019;8:568–574

KLF4 coordinates corneal epithelial apicobasal polarity and plane of cell division, and is downregulated in ocular surface squamous neoplasia

“…In contrast, the Klf4 Δ/ΔCE corneas displayed a tilt in the plane of division favoring vertical plane of division expected to result in symmetrical daughter cells that retain the potential to further proliferate. This results in excessive proliferation and compromised differentiation as observed in different tumors involving mutations and/or deletions of KLF4 (25,(45)(46)(47). Consistent with this scenario, the absence of Klf4 potentially drives the Klf4 Δ/ΔCE CE towards OSSN, a group of ocular surface tumors characterized by hyperproliferation and aggressive migration (48).…”

Single-cell RNA-seq reveals a concomitant delay in differentiation and cell cycle of aged hematopoietic stem cell

“…Although, we could not directly address the question of self-renewal, we can argue based on our regulon and cell cycle analyses that old LTHSCs have kept their capacity to self-renew and did not reach a state of complete dormancy but reduced their proliferation linked to differentiation. Interestingly, we could associate this reduced and age-related proliferation/differentiation potential to a high level of Klf6 and Mycn activity, known to contribute to the stemness and self-renewal of different stem cells 52 and a high level of Gfi1b activity known to promote self-renewal of HSC 53 . One interesting outcome of our analysis is the link between the delay in differentiation and cell cycle activity changes of old HSPCs.…”

The role of KLF14 in multiple disease processes

“…Multiple studies have indicated that KLFs are involved in the many different physiological and pathological processes. In recent studies, KFLs have been reported to play a critical role in the maintenance of homeostasis of many critical systems, including cardiovascular, cerebral, renal, immune, digestive, respiratory, and hematopoietic system . For example, in hepatobiliary system, KLF2 and KLF11 are shown to play roles in the hepatic fibrogenesis.…”

“…In recent studies, KFLs have been reported to play a critical role in the maintenance of homeostasis of many critical systems, including cardiovascular, cerebral, renal, immune, digestive, respiratory, and hematopoietic system. [2][3][4][5][6][7][8] For example, in hepatobiliary system, KLF2 and KLF11 are shown to play roles in the hepatic fibrogenesis. KLF4, KLF6, KLF8, KLF9, and KLF17 are shown to be involved in the pathogenesis of hepatocellular carcinoma (HCC) by modulating the invasion, proliferation, apoptosis, and migration of the cancer cells.…”