Article

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

Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute for Experimental Cancer Research (ISREC), Station 19, 1015 Lausanne, Switzerland.
Immunity (Impact Factor: 19.75). 11/2010; 33(5):671-84. DOI: 10.1016/j.immuni.2010.11.014
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
100 Views
 · 
0 Downloads
  • Source
    • "The activation of Notch receptor releases its intracellular domain (NotchIC), which translocates to the nucleus, forms a complex with transcription factor CSL and activates transcription of target genes. Hes1 is a canonical direct target of Notch/CSL that is required both for normal T cell development and Notch-induced T-ALL (Wendorff et al., 2010). Overexpression of NotchIC in murine hematopoietic progenitors is sufficient to initiate transplantable T-ALL, which originates from highly proliferative CD4 À CD8 À double-negative (DN) stage 4 (DN4) and CD4 À CD8 + immature single-positive (ISP) thymocytes (Li et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.
    Cell Reports 01/2014; 6(3). DOI:10.1016/j.celrep.2014.01.007 · 8.36 Impact Factor
  • Source
    • "The activation of Notch receptor releases its intracellular domain (NotchIC), which translocates to the nucleus, forms a complex with transcription factor CSL and activates transcription of target genes. Hes1 is a canonical direct target of Notch/CSL that is required both for normal T cell development and Notch-induced T-ALL (Wendorff et al., 2010). Overexpression of NotchIC in murine hematopoietic progenitors is sufficient to initiate transplantable T-ALL, which originates from highly proliferative CD4 À CD8 À double-negative (DN) stage 4 (DN4) and CD4 À CD8 + immature single-positive (ISP) thymocytes (Li et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Figure optionsView in workspaceDownload full-size imageDownload as PowerPoint slide
  • Source
    • "Notch signaling and its receptor play an important role in tumor occurrence and development [7-9]. Because this pathway signals for cell apoptosis and revascularization in renal carcinoma, many researchers focus on the inhibition of Notch. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Our study is to research the effect of inhibited ADAM-17 expression through the Notch pathway in renal carcinoma. Methods Immunohistochemistry and western blot were used to examine the expression of ADAM-17 protein in renal cancer tissues. Proliferation and cell invasion of 786-o cells, as well as OS-RC-2 cells, after treatment with two different inhibitors of the Notch pathway, were examined by CCK-8 assay and Transwell assay, respectively. 786-o cell apoptosis was measured using the FCM test. Results ADAM-17 was highly expressed in RCC tissues. Compared with blocking γ-secretase, a known mechanism of impairing Notch, blockade of ADAM-17 more effectively down-regulated the expressions of Notch1 and HES-1 proteins. Similarly, we found that the ADAM-17 inhibitor, Marimastat, could more efficiently reduce renal cell proliferation and invasive capacity in comparison with the γ-secretase inhibitor DAPT when used at the same dose. Similar results were obtained when apoptosis of 786-o was measured. Conclusion Compared with γ-secretase, inhibition of ADAM-17 expression more effectively inhibits Notch pathway-mediated renal cancer cell proliferation and invasion. ADAM-17 may be a new target for future treatment of renal carcinoma.
    Journal of Experimental & Clinical Cancer Research 05/2013; 32(1):26. DOI:10.1186/1756-9966-32-26 · 4.23 Impact Factor
Show more