NOTCH signaling pathway and Acute Lymphoblastic Leukemia - PowerPoint PPT Presentation

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NOTCH signaling pathway and Acute Lymphoblastic Leukemia

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NOTCH signaling pathway and Acute Lymphoblastic Leukemia Cecilia Varnagy-Moskovitz Definitions. Leukemia: group of bone marrow diseases involving an uncontrolled ... – PowerPoint PPT presentation

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Title: NOTCH signaling pathway and Acute Lymphoblastic Leukemia


1
NOTCH signaling pathway and Acute Lymphoblastic
Leukemia
  • Cecilia Varnagy-Moskovitz

2
Definitions.
  • Leukemia group of bone marrow diseases
    involving an uncontrolled increase in WBC.
    (Medical Encyclopedia).
  • Acute fast development of the disease.
  • Lymphocytic is develop from lymphocytes.

3
Definitions
  • Hematopoiesis process of development of blood
    cells.
  • Second messenger system where an intracellular
    signal is generated in response to an
    intercellular stimulation.
  • Ligand molecule that binds to another.

4
Definitions
  • NOTCH gene family that encodes single pass
    trans-membrane receptors able to transduce
    intercellular signals involved in cells-fate
    determination. (Kojika).
  • JAGGED1 important ligand for NOTCH signaling
    pathways.
  • Signal pathway transference of information
    through a channel, mediated by second messengers.

5
Symptoms of Leukemia.
  • Fevers or night sweats.
  • Headache.
  • Bleeding.
  • Swollen lymph nodes.
  • Frequent infections.
  • Feeling weak or tired.
  • Pain in bones or joints.
  • Weight loss.

6
Diagnosis of leukemia.
  • Physical exam.
  • Blood test.
  • Biopsy.
  • Cytogenetics.
  • Spinal tap.
  • Chest X-ray.

7
Treatment for Leukemia.
  • Chemotherapy.
  • Biological therapy.
  • Bone marrow transplantation.

8
A wide role for NOTCH1 signaling in acute leukemia
  • Chiaramonte, Raffaella
  • et al.

9
NOTCH signaling and acute leukemia
  • Basic terms we need to know
  • T-acute lymphoblastic leukemia (T-ALL)
  • Acute myelogenic leukemia (AML)
  • B-cell precursor ALL (BCP-ALL)
  • Delta/Serrate/ Lag2 ligands (DSL)

10
NOTCH signaling and ALL
  • NOTCH pathway has a role in the process of
    hematopoiesis.
  • NOTCH1 is related to the development of
    thymocites.
  • NOTCH1 needs to be active in earliest stages of
    T-cell commitment in thymus to be able to develop
    T-lymphocytes.
  • If this doesnt happen B-lineage will be
    developed.

11
NOTCH signaling and ALL
  • NOTCH1 has also important role in signaling
    alterations in pathogenesis of T-ALL.
  • T-ALL patients present a translocation that leads
    to over expression of NOTCH1
  • NOTCH pathway is activated in T-ALL cell lines.

12
Materials and Methods
  • Pediatric patients
  • 32 children with T-ALL
  • 25 with BCP-ALL
  • 20 with AML
  • Cell lines used were T-ALL and B-cell derived
    leukemia/lymphoma.

13
Materials and Methods
  • Extraction of RNA and retro-transcripted.
  • PCR test and amplifications.
  • Amplified DNAs separated by electrophoresis.
  • Results analyzed by ANOVA (analysis of variance)
    test

14
Question!!
  • What is the gene expression involved in NOTCH
    pathway activity related with three groups of
    patients T-ALL, BCP-ALL, and AML???

15
Hypothesis.
  • Ho gene expression values are equal across the
    different cell types.
  • H1 at least two cell types gene expression
    values are different.
  • For rejection of H0 Plt0.01

16
Comparison test
  • To know which particular population differs from
    others.
  • To have a significant difference Plt0.05.

17
Test and results
  • Analysis of T-ALL cell lines and DSL ligands.
    (control lymphoma cell line)
  • In all T-ALL cell lines expressed at least one
    ligand.
  • Comparison of expression values of NOTCH related
    genes (NOTCH1, HES1, pT? , and JAGGED1)

18
Results
  • After comparison of the three groups
  • NOTCH1 levels in T-ALL and AML were equivalent,
    but higher than BCP-ALL (Plt0.01)
  • For HES1 and pT?, T-ALL present highest levels of
    expression, compared to AML and BCP-ALL.
  • JAGGED1 is more frequent in AML than T-ALL and
    BCP-ALL.

19
Conclusions.
  • Cell fate is regulated by NOTCH1
  • NOTCH1 interferes in cell differentiation
  • NOTCH1 helps avoid apoptosis of T-cell lineage
    differentiation
  • T-ALL present high levels of NOTCH1
  • High level of pathway activity is related to
    NOTCH ligands

20
Conclusions
  • JAGGED1 expression related to differentiation in
    hematopoietic progenitors.
  • JAGGED1 has no relation with NOTCH pathway
  • NOTCH1 has an important role in T-ALL

21
Thank you
  • Questions
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