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

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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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Presentation Transcript
slide1

Notch1

And

T-All

(T-cell Acute Lymphoblastic Leukemia)

Katie Lozada

slide2

How Notch was discovered

-Discovered in Drosophila 1917 by Thomas Hunt Morgan

-Notch pathway is highly conserved between Drosophila and humans

slide3

Notch1 is a cell surface receptor

-plays a key role in cell fate decisions

slide4

Overview of the Notch Pathway

Ligand binds to Notch extracellular domain

 induces proteolytic cleavage

 releases intracellular domain

 enters nucleus, activate CSL

 alter gene expression!

slide5

Overview of Notch Pathway

Maillard et al. Fig 1.

slide6

Notch Signaling can have diverse effects

Stem Cells

Bipotent Thymocytes

Tcell

Bcell

Inhibit Differentiation

Promote Tcell fate

Radtke et al. Fig 2.

slide7

Notch Signaling can have diverse effects

Skin Cells

Tcells

Terminal differentiation

ONCOGENE

Radtke et al. Fig 2.

slide8

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

This precluded analysis of its role in the lymphocyte lineage

slide9

Specifically knock out Notch 1 in adult mice

After its roles in embryonic development are over

slide10

Interferon

Promoter

Korf et al. Fig. 4-17.

slide13

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

slide15

Oncogenic Activity of Notch

Maillard et al. Fig. 1

slide16

Oncogenic Activity of Notch1

Oncogenic signal  differentiation block

inhibition of cell cycle arrest and apoptosis

slide17

T-ALL is a cancer of Lymphoblasts

-Uncontrolled T-cell Proliferation

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

slide18

Translocation causes constitutively active Notch1

Translocation between Notch1 gene and TCRβ locus

Constitutively active

slide19

Notch Tumorigenesis

-maintains precursor cells in proliferating and undifferentiated state

slide20

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

slide21

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

slide22

Treatment for T-ALL

-Systemic disease requires multi-drug chemotherapy

-High survival rate among treated patients

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