RESUMEN

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.

Asunto(s)

Citocinas/genética , Transición Epitelial-Mesenquimal/genética , Hematopoyesis Extramedular/genética , Proteínas de Homeodominio/genética , Mielofibrosis Primaria/genética , Proteínas Represoras/genética , Esplenomegalia/genética , Adulto , Animales , Secuencia de Bases , Médula Ósea/metabolismo , Médula Ósea/patología , Diferenciación Celular , Linaje de la Célula/genética , Citocinas/metabolismo , Regulación de la Expresión Génica , Humanos , Quinasas Janus/genética , Quinasas Janus/metabolismo , Ratones , Ratones Noqueados , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Mutación , Mielofibrosis Primaria/metabolismo , Mielofibrosis Primaria/patología , Proteínas Represoras/deficiencia , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Bazo/metabolismo , Bazo/patología , Esplenomegalia/metabolismo , Esplenomegalia/patología , Células Madre/metabolismo , Células Madre/patología , Transcripción Genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc