notch and t-cell acute lymphoblastic leukemias by ana ruth cerna march 2 th, 2006

Notch and T-cell acute Notch and T-cell acute Lymphoblastic leukemiasLymphoblastic leukemias

byby

Ana Ruth CernaAna Ruth Cerna

March 2March 2thth, 2006, 2006

Intro to NotchIntro to Notch

Notch proteins:Notch proteins: Transmembrane receptors w/ different Transmembrane receptors w/ different

domains.domains. Ligands include: Jagged and Delta-likeLigands include: Jagged and Delta-like

Synthesized as precursor to be Synthesized as precursor to be proteolytically processedproteolytically processed

Work in:Work in: Lateral signaling that influence cell-fate Lateral signaling that influence cell-fate

decisions. Inductive cell fate decisions. decisions. Inductive cell fate decisions. ProliferationProliferation ApoptosisApoptosis

Notch SignalingNotch Signaling

Role of Notch in T-cell Role of Notch in T-cell developmentdevelopment

Part of T-cell development at Part of T-cell development at various stages:various stages: T/B cell fate determination by T/B cell fate determination by

Notch1 signalingNotch1 signaling// and and // lineage decision lineage decision And CD4/CD8 lineage And CD4/CD8 lineage

commitmentcommitment

T-Cell DevelopmentT-Cell Development

http://www.med.upenn.edu/immun/images/PearGRAPHIC.gif

T-Cell DevelopmentT-Cell Development

http://www.niaid.nih.gov/dir/labs/LCMI/development.gif

T-Cell Acute Lymphoblastic T-Cell Acute Lymphoblastic Leukemia (T-ALL) & NotchLeukemia (T-ALL) & Notch Constant Notch activation caused by Constant Notch activation caused by

point mutations, translocations and point mutations, translocations and other mechanisms. other mechanisms.

Over expression of Notch:Over expression of Notch: Enhances thymocyte survival and Enhances thymocyte survival and

proliferation.proliferation. Increased number of immature T Cell Increased number of immature T Cell

progenitors. Increases likelihood of progenitors. Increases likelihood of other mutations that could affect other mutations that could affect development.development.

Mice models—inactivation of Mice models—inactivation of Notch1Notch1

Immunity, Vol. 10, 547-558, May, 1999

Inactivation of Notch1 leads to Inactivation of Notch1 leads to retarded growthretarded growth

Immunity, Vol. 10, 547-558, May, 1999

Constitutive Activation of Notch Constitutive Activation of Notch and relationship to T-ALLand 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. 2004 November; 24(21): 9265–9273. doi: 10.1128/MCB.24.21.9265-9273.2004

In SummaryIn Summary

Notch influences cancer Notch influences cancer development by affecting cell fate, development by affecting cell fate, proliferation, and apoptosis.proliferation, and apoptosis.

Mouse models provide a great way Mouse models provide a great way to study Notch signaling pathway.to study Notch signaling pathway.

Interesting to point out that Notch is also Interesting to point out that Notch is also involved in other human cancers such as: involved in other human cancers such as: pancreatic cancer, medulloblastoma Y pancreatic cancer, medulloblastoma Y mucoepidermoid carcinoma.mucoepidermoid carcinoma.

RESH_Story_Notch_Full by Thomas Schmitt.jpg