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