Hes1 Is a Critical but Context-Dependent Mediator of Canonical Notch Signaling in Lymphocyte Development and Transformation

Christelle Dubey, Ute Koch, Freddy Radtke, Agnieszka Anna Wendorff, Silvia Wirth
Elsevier, 2010
Article

Résumé

Although canonical Notch signaling regulates multiple hematopoietic lineage decisions including T cell and marginal zone B cell fate specification, the downstream molecular mediators of Notch function are largely unknown. We showed here that conditional inactivation of Hes1, a well-characterized Notch target gene, in adult murine bone marrow (BM) cells severely impaired T cell development without affecting other Notch-dependent hematopoietic lineages such as marginal zone B cells. Competitive mixed BM chimeras, intrathymic transfer experiments, and in vitro culture of BM progenitors on Delta-like-expressing stromal cells further demonstrated that Hes1 is required for T cell lineage commitment, but dispensable for Notch-dependent thymocyte maturation through and beyond the beta selection checkpoint. Furthermore, our data strongly suggest that Hes1 is essential for the development and maintenance of Notch-induced T cell acute lymphoblastic leukemia. Collectively, our studies identify Hes1 as a critical but context-dependent mediator of canonical Notch signaling in the hematopoietic system.

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https://infoscience.epfl.ch/record/161449?ln=fr

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Notch1 receptor signaling is essential for T cell fate specification and physiological thymic T lymphocyte development. Its dysregulation and oncogenic activation are detected in almost 80% of pediatric patients suffering from T cell acute lymphoblastic leukemia (T-ALL). T-ALL is a hematological neoplasm arising from immature thymocytes. T cell factor 1 (Tcf1) is a crucial well-known transcription factor regulating the early stages of thymocyte maturation and Notch1 directly drives the expression of Tcf1 during normal T cell development. Here we assessed the role of Tcf1 in modulating chromatin topology which enables the initiation of T-ALL at the level of early hematopoietic progenitors. This allows for the discovery of stage-setting epigenetic regulators establishing a leukemia-prone chromatin landscape during Notch1-driven disease initiation. We found Tcf1 to be an essential mediator of Notch1 signaling during T-ALL induction. Inactivation of Tcf1 prevented leukemogenesis despite oncogenic Notch1 activation. Genomic analysis of hematopoietic progenitors revealed T cell lineage specification to be essential in T-ALL initiation prior to the appearance of phenotypic features of T cells. The expression of genes associated with the T cell lineage was dependent on Notch1 and Tcf1. Chromatin accessibility, chromosome conformation capture and ChIP-seq analysis revealed the co-regulatory epigenetic function of Notch1 and Tcf1 in imprinting a leukemic chromatin landscape. Epigenetic modulation of distal enhancers which regulate leukemic oncogenes has been well described in patient-derived T-ALL cells. The Notch1-Myc enhancer region was shown to be indispensable in the process of leukemogenesis. We have identified a novel regulatory locus, dependent on Tcf1 and Notch1, essential for the expression of Myc in pre-T-ALL cells. This genomic region termed Tcf1-regulated Myc enhancer (TMe) was highly conserved across species. TMe was essential for the transition of pre-leukemic cells to a transplantable full-blown T-ALL but was dispensable for the physiological development of T cells. After activation of the enhancer in hematopoietic progenitors, this regulatory site remained accessible and bound by Tcf1 in murine and human T-ALL cells. Tcf1 is therefore required for shaping the epigenetic landscape of hematopoietic progenitors overexpressing oncogenic Notch1, and thus regulates the expression of genes involved in leukemogenesis.

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Notch signaling is among one of the highly conserved developmental pathways. Because of its role in the regulation of stem cell self-renewal and cell fate decisions, Notch signaling maintains tissue homeostasis in several organs such as thymus, skin and intestine. The outcome of Notch signaling is tissue and cell-context dependent. However, the underlying mechanisms responsible for this tissue specificity are not fully understood yet. Therefore identification of signaling pathways that are able to modulate Notch signaling will enhance our understanding about the molecular mechanisms responsible for the tissue specific outcome of Notch signaling. In addition, an aberrant activation of Notch signaling is involved in many human cancers such as T-cell acute lymphoblastic leukemia (T-ALL) and breast cancer. The implication of Notch signaling in human cancers highlights the need to develop novel Notch signaling inhibitors as anti-cancer therapies. Therefore the aim of the present study was to identify novel human kinases and chemical compounds that are able to modulate Notch signaling. We have established a DL4:N1 coculture assay system to conduct high-through put screens of chemical compound libraries and of a siRNA library against human kinase genome. The latter screening campaign has led to the identification of PRKC, NRGN and CAMK2B kinases as positive regulators of the Notch pathway. siRNA or pharmacological mediated inhibition of these kinases led to a downregulation of Notch signaling. The screening of chemical compound libraries have led to the identification of three compounds that are able to block Notch signaling activation in in vitro assays. One of these inhibitors termed I3 was further investigated in in vivo studies to determine its effect on Notch-dependent T-cell and Marginal Zone B cell development in mice. Furthermore, the compound I3 has demonstrated a remarkable ability to block tumor progression in xenotransplant models of human T-ALL. In summary, the present study has identified several kinases and chemical compounds able to modulate Notch signalling. These candidates respectively constitute novel molecular targets and lead compounds, that can be exploited to develop targeted anti-cancer therapies.

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