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Notch and T-cell acute Lymphoblastic leukemias

Notch and T-cell acute Lymphoblastic leukemias. by Ana Ruth Cerna March 2 th , 2006. Intro to Notch. Notch proteins: Transmembrane receptors w/ different domains. Ligands include: Jagged and Delta-like Synthesized as precursor to be proteolytically processed Work in:

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Notch and T-cell acute Lymphoblastic leukemias

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  1. Notch and T-cell acute Lymphoblastic leukemias by Ana Ruth Cerna March 2th, 2006

  2. Intro to Notch • Notch proteins: • Transmembrane receptors w/ different domains. • Ligands include: Jagged and Delta-like • Synthesized as precursor to be proteolytically processed • Work in: • Lateral signaling that influence cell-fate decisions. Inductive cell fate decisions. • Proliferation • Apoptosis

  3. Notch Signaling

  4. Role of Notch in T-cell development • Part of T-cell development at various stages: • T/B cell fate determination by Notch1 signaling • / and / lineage decision • And CD4/CD8 lineage commitment

  5. T-Cell Development http://www.med.upenn.edu/immun/images/PearGRAPHIC.gif

  6. T-Cell Development http://www.niaid.nih.gov/dir/labs/LCMI/development.gif

  7. T-Cell Acute Lymphoblastic Leukemia (T-ALL) & Notch • Constant Notch activation caused by point mutations, translocations and other mechanisms. • Over expression of Notch: • Enhances thymocyte survival and proliferation. • Increased number of immature T Cell progenitors. Increases likelihood of other mutations that could affect development.

  8. Mice models—inactivation of Notch1 Immunity, Vol. 10, 547-558, May, 1999

  9. Inactivation of Notch1 leads to retarded growth Immunity, Vol. 10, 547-558, May, 1999

  10. Constitutive Activation of Notch and relationship to T-ALL Mol Cell Biol. 2004 November; 24(21): 9265–9273. doi: 10.1128/MCB.24.21.9265-9273.2004 Constitutive activation of Notch in mice as well as in T-ALL results in the overpopulation of immature t-cells in different tissues, which can be seen dramatically as an oversized spleen and mesenteric lymph node in the picture above.

  11. In Summary • Notch influences cancer development by affecting cell fate, proliferation, and apoptosis. • Mouse models provide a great way to study Notch signaling pathway. Interesting to point out that Notch is also involved in other human cancers such as: pancreatic cancer, medulloblastoma Y mucoepidermoid carcinoma.

  12. RESH_Story_Notch_Full by Thomas Schmitt.jpg

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