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The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling

Jin Li, Tamara Riedt, Steven Goossens, Carmen Carrillo García, Sabrina Szczepanski, Maria Brandes, Tim Pieters, Linne Dobrosch, Ines Gütgemann, Natalie Farla, Enrico Radaelli, Paco Hulpiau, Nikhil Mallela, Holger Fröhlich, Roberta La Starza, Caterina Matteucci, Tong Chen, Peter Brossart, Cristina Mecucci, Danny Huylebroeck, Jody J. Haigh and Viktor Janzen

Key Points

  • Zeb2 controls stem cell pool size and lineage fidelity.

  • Zeb2 deletion promotes a myeloproliferative phenotype resembling the early stage of primary myelofibrosis.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

Epithelial-to-mesenchymal-transition (EMT) is critical for normal embryogenesis and effective postnatal wound healing, but is also associated with cancer metastasis. SNAIL, ZEB, and TWIST families of transcription factors are key modulators of the EMT process, but their precise roles in adult hematopoietic development and homeostasis remain unclear. Here we report that genetic inactivation of Zeb2 results in increased frequency of stem and progenitor subpopulations within the bone marrow (BM) and spleen and that these changes accompany differentiation defects in multiple hematopoietic cell lineages. We found no evidence that Zeb2 is critical for hematopoietic stem cell self-renewal capacity. However, knocking out Zeb2 in the BM promoted a phenotype with several features that resemble human myeloproliferative disorders, such as BM fibrosis, splenomegaly, and extramedullary hematopoiesis. Global gene expression and intracellular signal transduction analysis revealed perturbations in specific cytokine and cytokine receptor–related signaling pathways following Zeb2 loss, especially the JAK-STAT and extracellular signal-regulated kinase pathways. Moreover, we detected some previously unknown mutations within the human Zeb2 gene (ZFX1B locus) from patients with myeloid disease. Collectively, our results demonstrate that Zeb2 controls adult hematopoietic differentiation and lineage fidelity through widespread modulation of dominant signaling pathways that may contribute to blood disorders.

  • Submitted May 5, 2016.
  • Accepted September 7, 2016.
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