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

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.

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

“…MBNL1 is upregulated by the KMT2A-AF9 fusion protein 34 , and genes encoding products involved in post-transcriptional processing ( SETD2 , U2AF1 and DICER1 ) harbored the sole recurrent mutation in several cases with rearrangements involving KMT2A , suggesting a functional role for altered splicing in pediatric leukemogenesis. Alterations in Zeb2 have been identified as cooperating events in murine CALM - AF10 leukemia models 35 , and Zeb2 -knockout mice develop myelofibrosis 36 , suggesting a fundamental role for this gene in the pathogenesis of AML.…”

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions

“…MBNL1 is upregulated by the KMT2A-AF9 fusion protein 33 , and genes involved in post-transcriptional processing (SETD2, U2AF1, DICER1) harbor the sole recurrent mutation in several KMT2A-rearranged cases, suggesting a functional role for altered splicing in pediatric leukemogenesis. Alterations in ZEB2 have been identified as cooperating events in murine CALM-AF10 leukemia models 34 while ZEB2 knockout mice develop myelofibrosis 35 , suggesting a fundamental role for this gene in the pathogenesis of AML.…”

Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate

“…Taken together, our findings suggest that Zeb2 activity may engage similar mechanisms to suppress alternative fates in multiple developing lineages. As lymphoid progenitors not presented here express and require Zeb2 (28), those cells and their progeny represent further avenues to explore the mechanisms by which this transcription factor regulates the development of immune lineages.…”

“…In oligodendrocyte precursors, where Zeb2 expression is low in abundance, activated Smads bind the coactivator histone acetyltransferase p300 and activate the expression of negative regulatory genes such as Id2 and Hes1; by contrast, in differentiating oligodendrocytes, expression of Olig1 and Olig2 induces Zeb2, which binds Smad-p300 complexes and represses expression of Id2 and Hes1 (24). Within the hematopoietic system, Zeb2 cooperates with Tbx21 (T-bet) to promote terminal maturation of natural killer (NK) cells and CD8 + T cells (25)(26)(27), and its inactivation results in broadly dysregulated hematopoiesis with prominent neutrophilia and loss of B cells and monocytes (28).…”