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.