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Notch1 And T-All (T-cell Acute Lymphoblastic Leukemia) Katie Lozada

Notch1 And T-All (T-cell Acute Lymphoblastic Leukemia) Katie Lozada. How Notch was discovered. -Discovered in Drosophila 1917 by Thomas Hunt Morgan -Notch pathway is highly conserved between Drosophila and humans. Notch1 is a cell surface receptor. -plays a key role in cell fate decisions.

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Notch1 And T-All (T-cell Acute Lymphoblastic Leukemia) Katie Lozada

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  1. Notch1 And T-All (T-cell Acute Lymphoblastic Leukemia) Katie Lozada

  2. How Notch was discovered -Discovered in Drosophila 1917 by Thomas Hunt Morgan -Notch pathway is highly conserved between Drosophila and humans

  3. Notch1 is a cell surface receptor -plays a key role in cell fate decisions

  4. Overview of the Notch Pathway Ligand binds to Notch extracellular domain  induces proteolytic cleavage  releases intracellular domain  enters nucleus, activate CSL  alter gene expression!

  5. Overview of Notch Pathway Maillard et al. Fig 1.

  6. Notch Signaling can have diverse effects Stem Cells Bipotent Thymocytes Tcell Bcell Inhibit Differentiation Promote Tcell fate Radtke et al. Fig 2.

  7. Notch Signaling can have diverse effects Skin Cells Tcells Terminal differentiation ONCOGENE Radtke et al. Fig 2.

  8. Notch1 knockout mice die at E 9.5 with defects in forming somites This precluded analysis of its role in the lymphocyte lineage

  9. Specifically knock out Notch 1 in adult mice After its roles in embryonic development are over

  10. Interferon Promoter Korf et al. Fig. 4-17.

  11. Loss of Notch1 in adults leads to reduction in size of thymus

  12. In the absence of Notch, T cell development is blocked MacDonald et al.Fig.2.

  13. Notch plays multiple roles in T cells Commitment to T-cell Lineage: -inactivated Notch1  no T cells, accumulate B -constitutively active Notch1  no B cells, accumulate T

  14. Notch plays multiple roles in T cells Grabher et al. Fig 3.

  15. Oncogenic Activity of Notch Maillard et al. Fig. 1

  16. Oncogenic Activity of Notch1 Oncogenic signal  differentiation block inhibition of cell cycle arrest and apoptosis

  17. T-ALL is a cancer of Lymphoblasts -Uncontrolled T-cell Proliferation -TCR breakpoints in 30%-35% of T-ALL cases

  18. Translocation causes constitutively active Notch1 Translocation between Notch1 gene and TCRβ locus Constitutively active

  19. Notch Tumorigenesis -maintains precursor cells in proliferating and undifferentiated state

  20. T-cell Acute Lymphoblastic Leukemia Notch activation leads to activation of as yet unknown genes involved in T cell fate It’s constitutive activation leads to  T cell proliferation and malignancy

  21. T-cell Acute Lymphoblastic Leukemia -T-ALL accounts for 10-15% of diagnosed Acute Lymphoblastic Leukemias -Mainly diagnosed in children (age 2-5) -Affects boys more than girls -Associated with large thymus

  22. Treatment for T-ALL -Systemic disease requires multi-drug chemotherapy -High survival rate among treated patients

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