The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling.
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.
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.
Jin
J
Li
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.
Tamara
T
Riedt
Inflammation Research Center, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent, Ghent, Belgium.
Steven
S
Goossens
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.
Carmen
C
Carrillo García
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.
Sabrina
S
Szczepanski
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.
Maria
M
Brandes
Inflammation Research Center, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Cancer Research Institute Ghent, Ghent, Belgium.
Tim
T
Pieters
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.
Linne
L
Dobrosch
Department of Pathology, University of Bonn, Bonn, Germany.
Ines
I
Gütgemann
Inflammation Research Center, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Natalie
N
Farla
Mouse and Animal Pathology Laboratory, Università degli Studi di Milano, Milan, Italy.|VIB Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium.
Enrico
E
Radaelli
Inflammation Research Center, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Paco
P
Hulpiau
Bonn-Aachen International Center for Information Technology, University of Bonn, Bonn, Germany.
Nikhil
N
Mallela
Bonn-Aachen International Center for Information Technology, University of Bonn, Bonn, Germany.
Holger
H
Fröhlich
Department of Medicine, Laboratory of Molecular Medicine, Centro Ricerche Emato-Oncologiche, University of Perugia, Perugia, Italy.
Roberta
R
La Starza
Department of Medicine, Laboratory of Molecular Medicine, Centro Ricerche Emato-Oncologiche, University of Perugia, Perugia, Italy.
Caterina
C
Matteucci
Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.
Tong
T
Chen
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.
Peter
P
Brossart
Department of Medicine, Laboratory of Molecular Medicine, Centro Ricerche Emato-Oncologiche, University of Perugia, Perugia, Italy.
Cristina
C
Mecucci
Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, University of Leuven, Leuven, Belgium.|Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands; and.
Danny
D
Huylebroeck
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
Jody J
JJ
Haigh
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, Bonn, Germany.
Viktor
V
Janzen
D000328:Adult; D000818:Animals; D001483:Base Sequence; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005786:Gene Expression Regulation; D006411:Hematopoiesis, Extramedullary / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D000074165:Zinc Finger E-box Binding Homeobox 2
D016207:Cytokines; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D050791:STAT Transcription Factors; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D053612:Janus Kinases; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3