Notch1 and pre-T-cell Acute Lymphoblastic Leukemia

(T-ALL)by Lindsey Wilfley

Acute Lymphoblastic Leukemia

• 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

• 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

Notch1 and its Ligands

Guidos, Cynthia J. Immunology

Normal Notch1 Signaling Pathway

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