Notch1 and its role in pre T-cell Acute Lymphoblastic Leukemia (ALL) - PowerPoint PPT Presentation

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Notch1 and its role in pre T-cell Acute Lymphoblastic Leukemia (ALL)

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Notch1 and its role in pre T-cell Acute Lymphoblastic Leukemia (ALL) By Rebecca Goodman What is Acute Lymphoblastic Leukemia? A cancer caused by the proliferation of ... – PowerPoint PPT presentation

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Title: Notch1 and its role in pre T-cell Acute Lymphoblastic Leukemia (ALL)


1
Notch1 and its role in pre T-cell Acute
Lymphoblastic Leukemia (ALL)
  • By Rebecca Goodman

2
What is Acute Lymphoblastic Leukemia?
  • A cancer caused by the proliferation of immature
    lymphocytes (pre T-cells and pre B-cells)
  • These cells are non-functional and accumulate in
    the body, inhibiting the function of normal cells

3
What does a T-cell do?
  • T-cells are white blood cells that are
    responsible for cell-mediated immunity and for
    the coordination of the immune response

4
  • 75 of Childhood Leukemias in the US are Acute
    Lymphoblastic Leukemia
  • 80 of ALLs are in B-cell progenitor cells
  • 15 of ALLs involve thymocytes
  • 5 involve cells of unknown origin
  • The majority of patients with pre T-cell ALL are
    white males

5
Normal Differentiation of Blood Cells
  • All blood cells originate from Haemopoietic Stem
    Cells found in the bone marrow

Pike, Marilyn
6
Non-functional thymocytes accumulate in the bone
marrow and organs and crowd out normal
hemopoietic cells leading to
  • Leukocytosis (high white blood cell count)
  • Bone Marrow Failure (evidenced by fatigue,
    pallor, bruising, hemorrhaging, infection, and
    fever)
  • Infiltration of spleen, lymph nodes, skin, and
    CNS

7
ALL is diagnosed by
  • Physical Examination
  • Complete Blood Count (CBC)
  • Bone Marrow Evaluation
  • The clinical onset of ALL is generally acute and
    rapidly progressing.

8
Treatments consist of
  • Chemotherapy to induce a complete remission
  • Post-remission chemotherapy and radiation of the
    CNS to improve the duration of remission

9
  • In the 1960s, less that 5 of children with ALL
    survived more than 5 years, while today, 85 of
    children with ALL live five years or more after
    diagnosis.

10
Notch1
  • First discovered in Drosophila and C. Elegans
  • A transmembrane receptor
  • Drosophila has one notch receptor whereas humans
    have four
  • Highly conserved
  • Ligands are Delta and Serrate/Jagged

11
Domains of Notch1 Protein
Guidos, Cynthia J. Immunology
12
Function of Notch1
  • Notch signaling pathways
  • Determine Binary Cell Fates
  • -ex. Neuronal vs. Epidermal Cell in Drosophila
  • Affects Survival/Proliferation of Committed
    Progenitors
  • -ex. Pre T-cells

13
Notch Pathway
Guidos, Cynthia J. Immunology
14
Mutations in the Notch Pathway can lead to
  • Acute Lymphoblastic Lymphoma (Notch1)
  • CADASIL (Notch3)
  • The Alagille Syndrome (Jagged1)
  • HPV-induced Cervical Cancer (Notch1)

15
The specific mutation that leads to ALL
  • A translocation between chromosomes 7 (contains
    T-cell receptor gene) and 9 (contains Notch1
    gene)
  • This puts part of the Notch1 gene downstream of
    the TCR gene promoter and leads to overexpression
    of the mutant Notch1

16
  • The mutant Notch1 protein has a truncated
    extracellular domain and is constitutively
    activated
  • Thus, the intracellular domain will undergo
    proteolysis without activation by a ligand
  • In the case of ALL this ultimately causes the
    thymocytes to remain undifferentiated while
    proliferating

17
Evidence that this Notch mutation leads to ALL
  • Pear et al infected the bone marrow of mice with
    mutant Notch1 using recombinant retroviruses.
    This induced pre T-cell leukemia in 50 of the
    animals.

18
Steps in Lymphoblast Differentiation at which
Notch1 might play a role
  • T-cell vs. B-cell
  • Rearrangement of receptors (two fates for
    T-cells)
  • Decision between Helper T-cell or Cytotoxic
    T-cell

19
Guidos, Cynthia J. Immunology
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