Acute Lymphocytic Leukemia and its signaling pathways

					Cecilia Varnagy-Moskovitz                            NOTCH signaling


Barry University.

Seminar (BIO 475)

Prof. Peter Lin

Research paper.




  Importance of NOTCH Signaling Pathways in Acute

                       Lymphocytic Leukemia




                                             Cecilia Varnagy-Moskovitz



                             March 2, 2005




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Cecilia Varnagy-Moskovitz                                                  NOTCH signaling


“Leukemia is a group of bone marrow diseases involving an uncontrolled increase in

white blood cells (leukocytes)”. (Medical Encyclopedia). The „acute‟ term means that

there is a fast development of the disease, and if this is not treated on time it could lead to

a fatal consequence in few months, this is because all blood cells are derivate from the

bone marrow, and when this cells cannot properly mature then leads to the acute

leukemia. „Lymphocytic‟ means that the leukemia is develop from a type of cells called

lymphocytes.



Signal pathway is the transference of information through a channel called a signal

pathway. A second messenger mediates each of the signals. (Medical Dictionary Online)



Second messenger, is a “system in which an intracellular signal is generated in response

to an intercellular primary messenger, such as a hormone”. (Medical Dictionary Online)



NOTCH is a “gene family that encodes single pass trans-membrane receptors able to

transduce intercellular signals involved in cell-fate determination”. (Kojika)

JAGGED1 important ligand for NOTCH signaling pathway. (Chiaramonte)



Hematopoiesis is the process of development of blood cells. (Medical Dictionary Online)

In leukemia what is happening is that the bone marrow is producing abnormal white

blood cells.

Ligand is a molecule that binds to another. (Medical Dictionary Online).




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Cecilia Varnagy-Moskovitz                                                  NOTCH signaling


At the beginning the function of this cells are normal, but in time they “may crowd out”

the rest of the normal blood cells (red blood cells, platelets, and white blood cells).

(National Cancer Institute).



The National Cancer Institute explains that the most common symptoms of leukemia are:

fevers or night sweats, frequent infections, feeling weak or tired, headache, bleeding and

bruising easily (bleeding gums, purplish patches in the skin, or tiny red spots under the

skin), pain in the bones or joints, swollen lymph nodes, especially in the neck or armpit,

and weight loss.



For the diagnosis of leukemia, if a patient present symptoms of leukemia, the doctor may

do a physical exam and ask about the patient's personal and family medical history. The

doctor also may order laboratory tests, especially blood tests.

Some tests and exams that can be done are: physical exam; where the lymph nodes,

spleen, and liver are checked for swelling, blood test; where the level of blood cells is

checked (in leukemia there is a high level of white blood cells and lower level of

platelets), biopsy; invasive method where the doctor removes a sample of bone marrow

and a pathologist analyze it (this is the only way to see if there are leukemia cells in the

bone marrow or not), cytogenetics; analysis of the chromosome of any cell from the

blood, bone marrow or lymph nodes, spinal tap; analysis of cerebrospinal fluid, and chest

x-ray; to reveal any signs of disease in the chest. (National Cancer Institute).




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Cecilia Varnagy-Moskovitz                                                  NOTCH signaling


There are few choices of treatment and the doctor is the right person to describe the

treatment choices and discuss the expected results. The available treatment is:

chemotherapy, biological therapy, or bone marrow transplantation. The choice of

treatment is made considering the type of leukemia and how extent is the disease.



In Chiaramonte‟s article, they investigate and then explained the importance of the

presence of NOTCH signaling in Acute Lymphoblastic Leukemia (T-ALL).

“NOTCH pathway has a role in the process of hematopoiesis affecting stem cells and

committed progenitors” (Milner). NOTCH1 is related to the development of thymocites

(thymus cells). As we know the lymphocytes can be develop on the thymus or in the bone

marrow and this process will make T or B lymphocyte. NOTCH1 needs to be active “in

the earliest stages of T-cell commitment in the thymus” to be able to develop T-

lymphocytes (Radtke). If this process doesn‟t happen like these, then the type of cell that

will be developed is from the B-lineage.

While NOTCH1 has a “fundamental role” in the development process of T-cells, also has

a “counterpart in the signaling alterations in the pathogenesis of T-cell acute

lymphoblastic leukemia (T-ALL)”. (Chiaramonte). T-ALL patients present a

translocation that leads to a “over expression of a constitutively active intracellular

portion of NOTCH1”. (Pear). The NOTCH pathway is activated in T-ALL cell lines,

independently of the translocation, when is compared to B-cell lymphomas or normal B

and T Lymphocytes. (Chiaramonte)




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Cecilia Varnagy-Moskovitz                                                NOTCH signaling


This study wanted to analyze the expression of genes involved in NOTCH pathway

activity in the different types of patients (T-ALL, B cell precursor ALL (BCP-ALL), and

acute myeloid leukemia (AML)). The final result was that the NOTCH pathway is

significant present in T-ALL in comparison with the other two groups of patients.



Materials and methods.

For the study they used pediatric patients: 32 children with T-ALL, 25 with BCP-ALL,

and 20 with AML. The cell lines used were: T-ALL and B-cell derived

leukemia/lymphoma.

To visualize how significant present were the ligands, they extracted the RNA and were

retro-transcripted. Then PCR test was performed and amplifications. The amplified

DNAs were separated by electrophoresis.

“The results were statistically analyzed by ANOVA (analysis of variance) test”

(Chiaramonte). They wanted to know if there were any difference in the “gene

expression” in the three different leukemia tested.



The hypothesis to be tested was:

“H0= gene expression values are equal across the different cell types; versus

H1= at least two cell types gene expression values are different.” (Chiaramonte)

For the rejection of the null hypothesis the P value has to be less than 0.01, concluding

that the “analyzed gene expression levels are different in, at least, two among the

analyzed populations” (Chiaramonte)




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Cecilia Varnagy-Moskovitz                                               NOTCH signaling


Then a comparison test was performed to determine “which particular population differs

from the others” (Chiaramonte). To have a significant difference the P value has to be

less than 0.05, and is not significant when P is grater than 0.05.



They made an analysis of the T-ALL cell lines and for all the DSL (Delta-/Serrate/Lag2)

ligands, using lymphoma cell line as controls.

The result was that in all T-ALL cell lines expressed at least one ligand encoding genes.

They made a comparison of the “expression values of NOTCH related genes (NOTCH1,

HES1, pT, and JAGGED1)” (Chiaramonte).

When they compared between the three populations the results were that the NOTCH1

levels of expression in T-ALL and AML were equivalent, but they are higher than BCP-

ALL (P<0.01). Measuring the gene expression of HES1 and pT (NOTCH1 pathway

signaling) result that T-ALL samples present highest levels of expression when it‟s

compared to AML and BCP-ALL.

For JAGGED1 the result was that this is more frequently present in AML than T-ALL

and BCP-ALL.




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Cecilia Varnagy-Moskovitz                                               NOTCH signaling


Conclusions.

      The cell fate (between Lymphocyte B or T and if is T-cell between CD4+ (helper)

       or CD8+ (citotoxic)) is regulated by NOTCH1. (Washburn)

      NOTCH1 also interferes in the differentiation process of the cells.

      NOTCH1 has a role in avoiding apoptosis of the cells in T-cell lineage

       differentiation. (Shelly)

      High levels of NOTCH1 gene expression are a common feature of T-ALL.

       (Chiaramonte)

      The fact that the NOTCH1 pathway is significant for T-ALL suggests that any

       problem in the regulation of this pathway leads to genetic alterations that cause

       deregulation of thymus cells development and leukemogenesis.

      A possible role for NOTCH ligands is inducing high level of pathway activity.

      Expression of JAGGED1 helps to the differentiation in hematopoietic progenitors.

      The high level of expression of JAGGED1 suggests that this ligand is important

       and maybe don‟t have any relation to NOTCH pathway activation (Chiaramonte)

      NOTCH1 signaling it has a very important role in acute leukemia, specially T-

       ALL.




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Cecilia Varnagy-Moskovitz                                                 NOTCH signaling


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.




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Cecilia Varnagy-Moskovitz                                              NOTCH signaling


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.




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