Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

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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.

Authors

Alhomidi Almotiri, Hamed Alzahrani, Juan Bautista Menendez-Gonzalez, Ali Abdelfattah, Badi Alotaibi, Lubaid Saleh, Adelle Greene, Mia Georgiou, Alex Gibbs, Amani Alsayari, Sarab Taha, Leigh-anne Thomas, Dhruv Shah, Sarah Edkins, Peter Giles, Marc P. Stemmler, Simone Brabletz, Thomas Brabletz, Ashleigh S. Boyd, Florian A. Siebzehnrubl, Neil P. Rodrigues