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ZEB1 is a close family member of ZEB2 but has remained more enigmatic concerning its roles in hematopoiesis. Here, we show using conditional loss-of-function approaches and bone marrow (BM) reconstitution experiments that ZEB1 plays a cell-autonomous role in hematopoietic lineage differentiation, particularly as a positive regulator of monocyte development in addition to its previously reported important role in T-cell differentiation. Analysis of existing single-cell (sc) RNA sequencing (RNA-seq) data of early hematopoiesis has revealed distinctive expression differences between<jats:italic>Zeb1<\/jats:italic>and<jats:italic>Zeb2<\/jats:italic>in hematopoietic stem and progenitor cell (HSPC) differentiation, with<jats:italic>Zeb2<\/jats:italic>being more highly and broadly expressed than<jats:italic>Zeb1<\/jats:italic>except at a key transition point (short-term HSC [ST-HSC]\u2794MPP1), whereby<jats:italic>Zeb1<\/jats:italic>appears to be the dominantly expressed family member. Inducible genetic inactivation of both<jats:italic>Zeb1<\/jats:italic>and<jats:italic>Zeb2<\/jats:italic>using a tamoxifen-inducible Cre-mediated approach leads to acute BM failure at this transition point with increased long-term and short-term hematopoietic stem cell numbers and an accompanying decrease in all hematopoietic lineage differentiation. Bioinformatics analysis of RNA-seq data has revealed that ZEB2 acts predominantly as a transcriptional repressor involved in restraining mature hematopoietic lineage gene expression programs from being expressed too early in HSPCs. ZEB1 appears to fine-tune this repressive role during hematopoiesis to ensure hematopoietic lineage fidelity. Analysis of Rosa26 locus\u2013based transgenic models has revealed that<jats:italic>Zeb1<\/jats:italic>as well as<jats:italic>Zeb2<\/jats:italic>cDNA-based overexpression within the hematopoietic system can drive extramedullary hematopoiesis\/splenomegaly and enhance monocyte development. Finally, inactivation of<jats:italic>Zeb2<\/jats:italic>alone or<jats:italic>Zeb1\/2<\/jats:italic>together was found to enhance survival in secondary MLL-AF9 acute myeloid leukemia (AML) models attesting to the oncogenic role of ZEB1\/2 in AML.<\/jats:p>","DOI":"10.1371\/journal.pbio.3001394","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T18:39:14Z","timestamp":1632335954000},"page":"e3001394","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":34,"title":["Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage 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