notch1 and pre-t-cell acute lymphoblastic leukemia (t-all) by lindsey wilfley
DESCRIPTION
Notch1 and pre-T-cell Acute Lymphoblastic Leukemia (T-ALL) by Lindsey Wilfley. Acute Lymphoblastic Leukemia. ALL comprises 1/3 of all pediatric cancers 10 - 15% of these cases are T-ALL Peak age: 2 –5 years More common in white males. What is T-ALL?. - PowerPoint PPT PresentationTRANSCRIPT
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Notch1 and pre-T-cell Acute Lymphoblastic Leukemia
(T-ALL)by Lindsey Wilfley
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Acute Lymphoblastic Leukemia
• ALL comprises 1/3 of all pediatric cancers
• 10 - 15% of these cases are T-ALL
• Peak age: 2 –5 years
• More common in white males
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What is T-ALL?
• A mutation in Lymphoid stem cells that causes over proliferation and accumulation of pre-T-cells (T lymphoblasts)
• These pre-T-cells are nonfunctional and over proliferate without differentiating into T cells
• Normal T-cells (T lymphocytes) are white blood cells that function in cell immunity
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Symptoms of T-ALL
• Mediastinal Masses
• High WBC count
• Frequent Infections
• Anemia
• Bruise easily
• Fatigue and Anorexia
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So What Is Notch1?• Transmembrane receptor • 2 main regions: extracellular component (ECN1)
and an intracellular component (ICN1)• Ligands – members of the Delta family and the
Serrate/Jagged family• First discovered in Drosophila but is highly
conserved• Homologs have been found in C.Elegans and in
humans
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Function of Notch1• Signaling involved in cell proliferation,
enhanced cell survival and differentiation in many different tissues
• Examples:
- neurogenesis
- wing/ limb-bud development
- somite formation
- T-cell differentiation
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Notch1 and its Ligands
Guidos, Cynthia J. Immunology
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Normal Notch1 Signaling Pathway
Guidos, Cynthia J. Immunology
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ICN1 binds to transcription factors that activate:
• general target genes - HES family
• and tissue specific genes – these determine what type of T-cells will develop!!
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Lymphoid stem cell differentiation
Normal differentiation into B and T lymphocytes
Pike, Marilyn
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Notch signaling occurs at 3 stages in T-cell development
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Notch1 Knockout Mice
• Inactivation of the entire gene – early embryonic lethal phenotype
• Conditional inactivation of gene in bone marrow precursor cells – block in T-cell development
• Repression of Notch1 in bone marrow cells – increased cells in γδ lineage
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Conditional Notch1 knockout mice
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Oncogenic Notch1
• Translocation between chromosomes 7 and 9
• Places part of the Notch1 gene downstream from the enhancer for the T-cell antigen receptor (TCR) gene
• Transcribes a Notch1 protein with a truncated ECN
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• The ICN1 is able to translocate to the nucleus without binding to a ligand
• Gain of Function – constitutively active Notch1 protein
• Over proliferation of undifferentiated pre-T-cells results in T-ALL
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Pre-T-Cells in Mutant Form• Pre-T-cells accumulate in
the bone marrow and inhibit the function of normal red and white blood cells
• Non-functional pre-T-cells can also migrate and form tumors in other areas of the lymph system and the central nervous system
http://www.emedicine.com/ped/topic2587.htm
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Evidence of Notch1 role in T-ALL
• Over expression of ICN1 in pre-T-cells of transgenic mice – causes thymic lymphomas
• Transduction of truncated human Notch1 into the bone marrow cells of wild type mice – causes T-cell lymphoma
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Treatments
• Current cure rates exceed 70%
• Chemotherapy – initial remission (95% success rate) and continued for up to 2-3 years to prevent relapse
• Stem cell transplantation for high risk cases