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Notch1 and pre-T-cell Acute Lymphoblastic Leukemia (T-ALL) by Lindsey Wilfley

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?.

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Notch1 and pre-T-cell Acute Lymphoblastic Leukemia (T-ALL) by Lindsey Wilfley

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  1. Notch1 and pre-T-cell Acute Lymphoblastic Leukemia (T-ALL)by Lindsey Wilfley

  2. 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

  3. 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

  4. Symptoms of T-ALL • Mediastinal Masses • High WBC count • Frequent Infections • Anemia • Bruise easily • Fatigue and Anorexia

  5. 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

  6. 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

  7. Notch1 and its Ligands Guidos, Cynthia J. Immunology

  8. Normal Notch1 Signaling Pathway Guidos, Cynthia J. Immunology

  9. 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!!

  10. Lymphoid stem cell differentiation Normal differentiation into B and T lymphocytes Pike, Marilyn

  11. Notch signaling occurs at 3 stages in T-cell development

  12. 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 Notch1 Knockout Mice

  13. Conditional Notch1 knockout mice

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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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