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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 Presentation
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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?
• 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
Symptoms of T-ALL
• Mediastinal Masses
• High WBC count
• Frequent Infections
• Anemia
• Bruise easily
• Fatigue and Anorexia
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
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
Notch1 and its Ligands
Guidos, Cynthia J. Immunology
Normal Notch1 Signaling Pathway
Guidos, Cynthia J. Immunology
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!!
Lymphoid stem cell differentiation
Normal differentiation into B and T lymphocytes
Pike, Marilyn
Notch signaling occurs at 3 stages in T-cell development
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
Conditional Notch1 knockout mice
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
• 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
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
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
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
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