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

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

Notch Signaling

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

T-Cell Development

T-Cell Development

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

Mice models—inactivation of Notch1 Immunity, Vol. 10, , May, 1999

Inactivation of Notch1 leads to retarded growth Immunity, Vol. 10, , May, 1999

Constitutive Activation of Notch and relationship to T-ALL 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. Mol Cell Biol November; 24(21): 9265–9273. doi: /MCB

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

RESH_Story_Notch_Full by Thomas Schmitt.jpg