Abstract
Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal transition (EMT) transcription factor, confers properties of “stemness,” such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system as a well-established paradigm of stem cell biology to evaluate Zeb1-mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knock out (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid-onset thymic atrophy and apoptosis-driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multilineage differentiation block were observed in Zeb1-KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multilineage differentiation genes and of cell polarity consisting of cytoskeleton-, lipid metabolism/lipid membrane–, and cell adhesion–related genes. Notably, epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1-KO HSCs, which correlated with enhanced cell survival, diminished mitochondrial metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEB1 expression was downregulated in AML patients, and Zeb1 KO in the malignant counterparts of HSCs — leukemic stem cells (LSCs) — accelerated MLL-AF9– and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Thus, Zeb1 acts as a transcriptional regulator in hematopoiesis, critically coordinating HSC self-renewal, apoptotic, and multilineage differentiation fates required to suppress leukemic potential in AML.
Highlights
Epithelial-mesenchymal transition (EMT) is a complex process that organizes specific changes in cellular fate and phenotype and is usually accompanied by loss of cell polarity and adhesion and increased locomotion [1]
Deregulation of Zeb1 activity has been implicated in multiple cancer types and, in these settings, Zeb1 acts as an instigator of the activity of cancer stem cells, a subset of cancer cells driving therapy resistance and metastasis, which cause fatality [42, 43]
In stem cells of the hematopoietic system, we find that acute conditional deletion of Zeb1 causes a profound cell-autonomous self-renewal defect and differentiation block across all lineages after transplantation and deregulates a transcriptional program associated with cell polarity
Summary
Epithelial-mesenchymal transition (EMT) is a complex process that organizes specific changes in cellular fate and phenotype and is usually accompanied by loss of cell polarity and adhesion and increased locomotion [1]. EMT is an important step in embryonic development and regeneration, which largely promotes a program of cellular plasticity and migration [2]. This program is regulated by specific transcription factors (TFs), such as members of the ZEB, SNAI, and TWIST families. To this end, Zeb, a zinc finger TF that binds to E-box motifs, has been implicated in myogenesis [3,4,5,6], neuronal development and differentiation [7,8,9,10], postgastrulation embryogenesis [11] and T cell development [12, 13]. While it is established that Zeb regulates expression of multiple stem cell–associated TFs, including those with oncogenic potential, such as BMI1, KLF4, and SOX2 [19, 21], and that loss of Zeb promotes cellular differentiation during development of the embryonic CNS [9] and skeletal muscle [22], the wider role of Zeb in normal stem cell–fate decisions remains unclear
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