Zeb1 Modulates Hematopoietic Stem Cell Fates Required For Suppressing Acute Myeloid Leukemia

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal transition (EMT) transcription factor, confers properties of "sternness," such as self-renewal, in cancer. Yet little is known about the function of Zebi in adult stem cells. Here, we used the hematopoietic system as a well-established paradigm of stem cell biology to evaluate Zebi-mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knock out (KO) Zebi in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zebi 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 Zebi-K0 HSCs. Loss of Zebi 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 Zeb1-1(0 HSCs, which correlated with enhanced cell survival, diminished mitochondria) metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEI31 expression was downregulated in AML patients, and Zebi KO in the malignant counterparts of HSCs - leukemic stem cells (LSCs) - accelerated MLL-AF9- and Meisla/Hoxa9-driven AML progression, implicating Zebi as a tumor suppressor in AML LSCs. Thus, Zeb7 acts as a transcriptional regulator in hematopoiesis, critically coordinating HSC self-renewal, apoptotic, and multilineage differentiation fates required to suppress leukemic potential in AML.