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Notch1 and its oncogenic role in T-ALL

Notch1 and its oncogenic role in T-ALL. Kyle Smith Biol 445 Spring 2013. Notch1 protein s tructure. Single-pass transmembrane protein. Extracellular domain EGF-like repeats binds Transmembrane domain Intercellular domain. Notch1 signaling p athway.

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Notch1 and its oncogenic role in T-ALL

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  1. Notch1 and its oncogenic role in T-ALL

  2. Kyle Smith Biol 445 Spring 2013

  3. Notch1 protein structure

  4. Single-pass transmembrane protein • Extracellular domain • EGF-like repeats • binds • Transmembrane domain • Intercellular domain

  5. Notch1 signaling pathway

  6. T-cell acute lympoblastic leukemia (T-ALL)

  7. T-lymphoblasts reproducing rapidly without differentiation • 15% of childhood and 25% of adult ALL cases • Current 5-year relapse-free survival rate is 75% in children and 50% in adults • Survival rates are poor in patients with resistant primary disease or who relapse

  8. Hematopoietic origins of T-ALL

  9. Oncogenic mutations of Notch1 in T-ALL

  10. wild type translocation leading to truncation mutation leading to destabilization of repeat complex responsible for maintaining resting configuration mutation preventing protection of extracellular cleavage site mutation displacing extracellular cleavage site outside repeat complex mutation increasing separation of repeat complex from the membrane mutation impairing the ability of the intracellular domain to be degraded in the nucleus Activating mutations!

  11. Mutations are most frequently found in exons encoding the N-terminal and C-terminal of the heterodimerization domain • Most Notch1 HD mutations are substitutions, deletions, and insertions which compromise a domain shielding Notch1’s cleavage, leading to ligand-hypersensitivity or ligand-independent NOTCH1 activation

  12. Notch1 target genes and T-ALL

  13. NOTCH1 is important for the commitment of stem cells to develop into functional T cells • particularly for the assembly of pre–T-cell–receptor complexes in immature thymocytes

  14. Activating Notch1 mutations are present in over 60% of human T-ALLs • In childhood T-ALL, Notch1 mutations have been found to be prognostic of: • favorable early treatment response • improved long-term prognosis

  15. 155 children with precursor T-ALL classified according to the presence or absence of Notch1 mutations Kaplan-Meier estimate of event-free survival at 4 years Cumulative incidence of relapse

  16. Prognostic and therapeutic value

  17. Small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease • Anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs show promise

  18. Small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease • Anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs are also promising

  19. References • NCBI. “NOTCH1 notch 1 [ Homo sapiens (human) ]”. <http://www.ncbi.nlm.nih.gov/gene/4851>. • Gannie Tzoneva and Adolfo A. Ferrando. “Recent Advances on NOTCH Signaling in T-ALL” Current Topics in Microbiology and Immunology (2012) 360: 163–182. • Raphael Kopan. “Notch Signaling”. Cold Spring HarbPerspectBiol 2012. • Li Xuan Tan. “Acute T-Cell Lymphoblastic Leukemia (T-ALL) & NOTCH1”. <http://tangen677s12.weebly.com/domains.html>. • Arnold S Freedman and Jon C Aster. “Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma”. UpToDate April 27, 2012. < http://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-precursor-t-cell-acute-lymphoblastic-leukemia-lymphoma>. • “Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia.” Blood Aug 15, 2006:1151-1157

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