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A wide role for NOTCH signaling in acute leukemia. Cecilia Varnagy-Moskovitz Chiaramonte, Raffaella, A. Basile, E. Tassi, E. Calzavarra, V. Cecchinato, V. Rossi, A. Biondi, P. Comi. 2005, A wide role for NOTCH1 signaling in acute leukemia. Cancer Letters 219: 113-120. Definitions.

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a wide role for notch signaling in acute leukemia

A wide role for NOTCH signaling in acute leukemia

Cecilia Varnagy-Moskovitz

Chiaramonte, Raffaella, A. Basile, E. Tassi, E. Calzavarra, V. Cecchinato, V. Rossi, A. Biondi, P. Comi. 2005, A wide role for NOTCH1 signaling in acute leukemia. Cancer Letters 219: 113-120

definitions
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.
  • Myelocytic: develop from myelocytes.
definitions3
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.
definitions4
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.
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.

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

AllRefer.com

treatment for leukemia
Treatment for Leukemia.
  • Chemotherapy.
  • Biological therapy.
  • Bone marrow transplantation.
notch signaling and acute leukemia
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)
notch signaling facts
NOTCH signaling facts.
  • 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 doesn’t happen B-lineage will be developed.
notch signaling facts11
NOTCH signaling facts.
  • 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.
materials and methods
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.

materials and methods13
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
question
Question!!
  • What is the gene expression involved in NOTCH pathway activity related with three groups of patients: T-ALL, BCP-ALL, and AML???
hypothesis
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 P<0.01

test and results
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)
rt pcr analysis of dsl ligands expression in t all cell lines
RT-PCR analysis of DSL ligands expression in T-ALL cell lines.

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*

+

* Control cells + Normalization gene

Chiaramonte et al.

rt pcr analysis of notch pathway related genes
RT-PCR analysis of NOTCH pathway related genes

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*

^

^

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* Target genes ^Ligands # Normalization gene

Chiaramonte et al.

rt pcr analysis of notch pathway related genes19
RT-PCR analysis of NOTCH pathway related genes.

*

*

^

^

#

*

*

^

^

#

* Target genes ^Ligands # Normalization gene

Chiaramonte et al.

comparison test
Comparison test
  • To know which particular population differs from others.
  • To have a significant difference P<0.05.
comparison test21
Comparison test.

Chiaramonte et al.

comparison test22
Comparison test.

Chiaramonte et al.

results
Results
  • After comparison of the three groups:
    • NOTCH1 levels in T-ALL and AML were equivalent, but higher than BCP-ALL (P<0.01)
    • 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.
notch role
NOTCH role.

Chiaramonte et al.

conclusions
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.
conclusions26
Conclusions
  • JAGGED1 expression related to differentiation in hematopoietic progenitors.
  • JAGGED1 has no relation with NOTCH pathway.
  • NOTCH1 has an important role in T-ALL.
references
References.

1.- American Cancer Society. What is Acute Myeloid Leukemia? January 01, 2005. February 2005. www.cancer.org

2.- Chiaramonte, R. et al. Differential regulation of NOTCH signal transduction in leukemia and lymphoma cells in culture. J. Cell. Biochem. 88. 2003:569-577.

3.- Janeway et al. Immunobiology. Garland Science Publishing. 2005.

4.- Kojika, S. et al.NOTCH Receptors in Hematopoiesis. Exp. Hematol. 29. 2001: 1041-1052.

5.- Medical Dictionary Online. Signal Pathway. 2005. February 2005. < http://www.online-medical-dictionary.org/omd.asp?q=signal+pathway>

6.- Medical Encyclopedia from Medline Plus. Leukemia. June 02, 2003. February 2005. http://www.nlm.nih.gov/medlineplus/ency/article/001299.htm

7.- Milner, L.A. et al. NOTCH as a Mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood 93. 1999: 2431-2444. February 2005. <http://www.bloodjournal.org/cgi/content/full/93/8/2431>

8.- National Cancer Institute. What you need to know about Leukemia. March 03, 2003. February 2005. <www.cancer.gov>

9.- Pear, W.S. et al. Exclusive development of T cell neoplasm in mice transplanted with bone marrow expressing activated NOTCH alleles. Exp. Med. 183. 1996:2283-2291. <http://www.jem.org/cgi/reprint/183/5/2283>

10.- Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of NOTCH1. Immunity 10. 1999:547-558.

11.- Shelly, L. et al. NOTCH-1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds. J. Cell. Biochem. 73. 1999:164.

12.- Washburn, T. et al. NOTCH activity influences the alpha/beta versus gamma/delta lineage decision. Cell 88. 1997:833-843.

thank you

Thank you

Questions