Transcript Notch 1 and pre-T-cell Acute Lymphoblastic Leukemia (T

Notch1 and pre-T-cell Acute
Lymphoblastic Leukemia
(T-ALL)
by Lindsey Wilfley
Acute Lymphoblastic Leukemia
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ALL comprises 1/3 of all pediatric cancers
10 - 15% of these cases are T-ALL
Peak age: 2 –5 years
More common in white males
What is T-ALL?
• A mutation in Lymphoid stem cells that
causes over proliferation and accumulation
of pre-T-cells (T lymphoblasts)
• These pre-T-cells are nonfunctional and
over proliferate without differentiating into
T cells
• Normal T-cells (T lymphocytes) are white
blood cells that function in cell immunity
Symptoms of T-ALL
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Mediastinal Masses
High WBC count
Frequent Infections
Anemia
Bruise easily
Fatigue and Anorexia
So What Is Notch1?
• Transmembrane receptor
• 2 main regions: extracellular component (ECN1)
and an intracellular component (ICN1)
• Ligands – members of the Delta family and the
Serrate/Jagged family
• First discovered in Drosophila but is highly
conserved
• Homologs have been found in C.Elegans and in
humans
Function of Notch1
• Signaling involved in cell proliferation,
enhanced cell survival and differentiation in
many different tissues
• Examples:
- neurogenesis
- wing/ limb-bud development
- somite formation
- T-cell differentiation
Domainsand
of Notch1
Protein
Notch1
its Ligands
Guidos, Cynthia J. Immunology
Guidos,
Guidos, Cynthia J. Immunology
Notch
Pathway
Normal Notch1 Signaling Pathway
Guidos, Cynthia J. Immunology
Guidos, Cynthia J. Immunology
ICN1 binds to transcription
factors that activate:
• general target genes - HES family
• and tissue specific genes – these determine
what type of T-cells will develop!!
Lymphoid stem cell differentiation
Normal differentiation
into B and T
lymphocytes
Pike, Marilyn
Notch signaling occurs at 3
stages in T-cell development
Notch1 Knockout Mice
• Inactivation of the entire gene – early
embryonic lethal phenotype
• Conditional inactivation of gene in bone
marrow precursor cells – block in T-cell
development
• Repression of Notch1 in bone marrow cells
– increased cells in γδ lineage
Conditional
Notch1 knockout
mice
Oncogenic Notch1
• Translocation between chromosomes 7 and
9
• Places part of the Notch1 gene downstream
from the enhancer for the T-cell antigen
receptor (TCR) gene
• Transcribes a Notch1 protein with a
truncated ECN
• The ICN1 is able to translocate to the
nucleus without binding to a ligand
• Gain of Function – constitutively
active Notch1 protein
• Over proliferation of undifferentiated
pre-T-cells results in T-ALL
Pre-T-Cells in Mutant Form
• Pre-T-cells accumulate in
the bone marrow and
inhibit the function of
normal red and white
blood cells
• Non-functional pre-T-cells
can also migrate and form
tumors in other areas of
the lymph system and the
central nervous system
http://www.emedicine.com/
ped/topic2587.htm
Evidence of Notch1 role in T-ALL
• Over expression of ICN1 in pre-T-cells of
transgenic mice – causes thymic
lymphomas
• Transduction of truncated human Notch1
into the bone marrow cells of wild type
mice – causes T-cell lymphoma
Treatments
• Current cure rates exceed 70%
• Chemotherapy – initial remission (95%
success rate) and continued for up to 2-3
years to prevent relapse
• Stem cell transplantation for high risk cases