Notch1 and its role in pre T-Notch1 and its role in pre T-cell Acute Lymphoblastic cell Acute Lymphoblastic

Leukemia (ALL)Leukemia (ALL)

By Rebecca By Rebecca GoodmanGoodman

What is Acute Lymphoblastic What is Acute Lymphoblastic Leukemia?Leukemia?

• A cancer caused by the proliferation A cancer caused by the proliferation of immature lymphocytes (pre T-cells of immature lymphocytes (pre T-cells and pre B-cells)and pre B-cells)

• These cells are non-functional and These cells are non-functional and accumulate in the body, inhibiting accumulate in the body, inhibiting the function of normal cellsthe function of normal cells

What does a T-cell do?What does a T-cell do?

• T-cells are white blood cells that are T-cells are white blood cells that are responsible for cell-mediated responsible for cell-mediated immunity and for the coordination of immunity and for the coordination of the immune responsethe immune response

• 75% of Childhood Leukemias in the 75% of Childhood Leukemias in the US are Acute Lymphoblastic US are Acute Lymphoblastic LeukemiaLeukemia

• 80% of ALL’s are in B-cell progenitor 80% of ALL’s are in B-cell progenitor cellscells

• 15% of ALL’s involve thymocytes15% of ALL’s involve thymocytes

• 5% involve cells of unknown origin5% involve cells of unknown origin

• The majority of patients with pre T-The majority of patients with pre T-cell ALL are white malescell ALL are white males

Normal Differentiation of Blood Normal Differentiation of Blood CellsCells• All blood cells originate from Haemopoietic All blood cells originate from Haemopoietic

Stem Cells found in the bone marrowStem Cells found in the bone marrow

Pike, MarilynPike, Marilyn

Non-functional thymocytes accumulate Non-functional thymocytes accumulate in the bone marrow and organs and in the bone marrow and organs and crowd out normal hemopoietic cells crowd out normal hemopoietic cells leading to…leading to…

• Leukocytosis (high white blood cell Leukocytosis (high white blood cell count)count)

• Bone Marrow Failure (evidenced by Bone Marrow Failure (evidenced by fatigue, pallor, bruising, hemorrhaging, fatigue, pallor, bruising, hemorrhaging, infection, and fever)infection, and fever)

• Infiltration of spleen, lymph nodes, skin, Infiltration of spleen, lymph nodes, skin, and CNSand CNS

ALL is diagnosed by…ALL is diagnosed by…

• Physical ExaminationPhysical Examination

• Complete Blood Count (CBC)Complete Blood Count (CBC)

• Bone Marrow EvaluationBone Marrow Evaluation

The clinical onset of ALL is generally The clinical onset of ALL is generally acute and rapidly progressing.acute and rapidly progressing.

Treatments consist of…Treatments consist of…

• Chemotherapy to induce a complete Chemotherapy to induce a complete remissionremission

• Post-remission chemotherapy and Post-remission chemotherapy and radiation of the CNS to improve the radiation of the CNS to improve the duration of remissionduration of remission

In the 1960’s, less that 5% of children In the 1960’s, less that 5% of children with ALL survived more than 5 years, with ALL survived more than 5 years, while today, 85% of children with ALL while today, 85% of children with ALL live five years or more after live five years or more after diagnosis.diagnosis.

Notch1Notch1

• First discovered in Drosophila and C. First discovered in Drosophila and C. ElegansElegans

• A transmembrane receptorA transmembrane receptor

• Drosophila has one notch receptor Drosophila has one notch receptor whereas humans have fourwhereas humans have four

• Highly conservedHighly conserved

• Ligands are Delta and Serrate/JaggedLigands are Delta and Serrate/Jagged

Domains of Notch1 ProteinDomains of Notch1 Protein

Guidos, Cynthia J. Guidos, Cynthia J. ImmunologyImmunology

Function of Notch1Function of Notch1

• Notch signaling pathways Notch signaling pathways 1.1. Determine Binary Cell FatesDetermine Binary Cell Fates

-ex. Neuronal vs. Epidermal Cell in -ex. Neuronal vs. Epidermal Cell in DrosophilaDrosophila

2.2. Affects Survival/Proliferation of Affects Survival/Proliferation of Committed Progenitors Committed Progenitors

-ex. Pre T-cells-ex. Pre T-cells

Notch PathwayNotch Pathway

Guidos, Cynthia J. Guidos, Cynthia J. ImmunologyImmunology

Mutations in the Notch Mutations in the Notch Pathway can lead to…Pathway can lead to…

• Acute Lymphoblastic Lymphoma Acute Lymphoblastic Lymphoma (Notch1)(Notch1)

• CADASIL (Notch3)CADASIL (Notch3)

• The Alagille Syndrome (Jagged1)The Alagille Syndrome (Jagged1)

• HPV-induced Cervical Cancer (Notch1)HPV-induced Cervical Cancer (Notch1)

The specific mutation that The specific mutation that leads to ALL…leads to ALL…

• A translocation between A translocation between chromosomes 7 (contains T-cell chromosomes 7 (contains T-cell receptor gene) and 9 (contains receptor gene) and 9 (contains Notch1 gene)Notch1 gene)

• This puts part of the Notch1 gene This puts part of the Notch1 gene downstream of the TCR gene downstream of the TCR gene promoter and leads to promoter and leads to overexpression of the mutant Notch1overexpression of the mutant Notch1

• The mutant Notch1 protein has a The mutant Notch1 protein has a truncated extracellular domain and is truncated extracellular domain and is constitutively activatedconstitutively activated

• Thus, the intracellular domain will Thus, the intracellular domain will undergo proteolysis without activation undergo proteolysis without activation by a ligandby a ligand

• In the case of ALL this ultimately In the case of ALL this ultimately causes the thymocytes to remain causes the thymocytes to remain undifferentiated while proliferating undifferentiated while proliferating

Evidence that this Notch Evidence that this Notch mutation leads to ALLmutation leads to ALL

• Pear et al infected the bone marrow Pear et al infected the bone marrow of mice with mutant Notch1 using of mice with mutant Notch1 using recombinant retroviruses. This recombinant retroviruses. This induced pre T-cell leukemia in ~50% induced pre T-cell leukemia in ~50% of the animals.of the animals.

Steps in Lymphoblast Steps in Lymphoblast Differentiation at which Notch1 Differentiation at which Notch1 might play a role…might play a role…

1.1. T-cell vs. B-cellT-cell vs. B-cell

2.2. Rearrangement of receptors (two Rearrangement of receptors (two fates for T-cells)fates for T-cells)

3.3. Decision between Helper T-cell or Decision between Helper T-cell or Cytotoxic T-cellCytotoxic T-cell

Guidos, Cynthia J. Guidos, Cynthia J. ImmunologyImmunology