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


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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


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


Overview of the Notch Pathway

Ligand binds to Notch extracellular domain

 induces proteolytic cleavage

 releases intracellular domain

 enters nucleus, activate CSL

 alter gene expression!


Overview of Notch Pathway

Maillard et al. Fig 1.


Notch Signaling can have diverse effects

Stem Cells

Bipotent Thymocytes

Tcell

Bcell

Inhibit Differentiation

Promote Tcell fate

Radtke et al. Fig 2.


Notch Signaling can have diverse effects

Skin Cells

Tcells

Terminal differentiation

ONCOGENE

Radtke et al. Fig 2.


Notch1 knockout mice die at E 9.5 with defects in forming somites

This precluded analysis of its role in the lymphocyte lineage


Specifically knock out Notch 1 in adult mice somites

After its roles in embryonic development are over


Interferon somites

Promoter

Korf et al. Fig. 4-17.




Notch plays multiple roles in T cells thymus

Commitment to T-cell Lineage:

-inactivated Notch1  no T cells, accumulate B

-constitutively active Notch1  no B cells, accumulate T


Notch plays multiple roles in T cells thymus

Grabher et al. Fig 3.


Oncogenic Activity of Notch thymus

Maillard et al. Fig. 1


Oncogenic Activity of Notch1 thymus

Oncogenic signal  differentiation block

inhibition of cell cycle arrest and apoptosis


T-ALL is a cancer of Lymphoblasts thymus

-Uncontrolled T-cell Proliferation

-TCR breakpoints in 30%-35% of T-ALL cases


Translocation causes constitutively active Notch1 thymus

Translocation between Notch1 gene and TCRβ locus

Constitutively active


Notch Tumorigenesis thymus

-maintains precursor cells in proliferating and undifferentiated state


T-cell Acute Lymphoblastic Leukemia thymus

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


T-cell Acute Lymphoblastic Leukemia thymus

-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


Treatment for T-ALL thymus

-Systemic disease requires multi-drug chemotherapy

-High survival rate among treated patients


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