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. 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

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