Park et al describe a novel KLF4-mediated pathway that promotes chromic myeloid leukemia (CML) stem cell (LSC) survival. Deletion of KLF4 in a mouse model of CML decreases LSC survival through repression of Dyrk2, resulting in c-Myc depletion and increased p53 activity.
In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition in AML cells reduced DNA accessibility and binding of these factors at PU.1 sites and redistributed PU.1 to promoters. Analysis of non-tumor hematopoietic cells revealed that similar effects also impair PU.1-dependent B cell and monocyte populations. Nevertheless, SWI/SNF inhibition induced profound therapeutic response in an immunocompetent AML mouse model as well as in primary human AML samples. In vivo, SWI/SNF inhibition promoted leukemic differentiation and reduced the leukemic stem cell burden in bone marrow but also induced leukopenia. These results reveal a variable therapeutic window for SWI/SNF blockade in AML and highlight important off-tumor effects of such therapies in immunocompetent settings.
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
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.
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