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Kick it up a Notch
The Role of Notch Signaling in T Cell
Differentiation and Cancer
Ryan Zimmerman
Notch Signaling Acts in
Many Cell Fate Choices

Notch knockout mice die before 10.5 days
in gestation

Cell death and patterning errors in lots of
tissues
Wild-type
http://www0.gsf.de/ieg/groups/genome/delta_notch.html
Notch pathway disrupted
Immune System Overview



Specific and non-specific protection from
bacteria, viruses and parasites.
All immune cells begin in the bone marrow.
Common precursors differentiate into two main
types of cells:
CD4+
http://www.niaid.nih.gov/final/immun/immun.htm
CD8+
Notch’s Niche
Binary cell-fate decisions in immune system precursor cells
MacDonald et al. (2001) Notch1 and T-cell Development: insights from
conditional knockout mice. Trends in Immunology. 22:155-160.
Notch Signaling in T/B Cell
Lineage Decision
Presenilin
MacDonald et al. (2001) Notch1 and T-cell Development: insights from
conditional knockout mice. Trends in Immunology. 22:155-160.
Disruption of Notch Signaling
Leads to Cancers

Leukemia: excessive proliferation and
incorrect development of leukocytes
Acute promyelocytic leukemia (peripheral blood smear, Wright's stain).
http://www.dorlands.com/def.jsp?id=12485436
Disruption of Notch Signaling is
Involved in a Specific Leukemia

T cell Acute Lymphoblastic Leukemia (T-ALL)
T-cell: display pre-T or T antigens
 Acute: sudden onset
 Lymphoblastic: involves immature T or B cells
not macrophages, etc.


1,450 of the 23,300 leukemia deaths in 2004
were from ALL
http://www.dorlands.com/def.jsp?id=12485436, http://www.leukemia-lymphoma.org/all_page?item_id=9346#_deaths
Genetics of T-ALL
Screpanti et al. (2003). Notch: a unifying target in T-cell acute
lymphoblastic leukemia? Trends in Molecular Medicine. Vol. 9: 30-35.
Notch3 is Overexpressed
in T-ALL
T cell leukemias
Bellavia et al. (2002). Combined expression of pT and Notch3 in T cell
leukemia identifies the requirement of preTCR
for leukemogenesis. PNAS. Vol. 99. 6: 3788-3793.
Non-T cell leukemias
Notch Signaling Components
Are Therapeutic Targets
Presenilin Inhibitors Induce Apoptosis in T-ALL Lines
Weng et al. (2003). Growth Surpression of Pre-T Acute
Lymphoblastic Leukemia Cells by Inhibition of Notch Signaling.
Molecular and Cell Biology. Vol. 23. 2: 655-664.
Summary


Notch signaling is involved in many types of cell
fate decisions
Critical for T cell differentiation


Misregulation is associated with T-ALL


2 binary decisions
Notch3 overexpression
T-ALL is responsive to therapies that target
elements of the Notch pathway

Presenilin inhibitors