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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
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