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Acute Myeloid Leukemia: A Paradoxical Phenomenon

                  Melissa Day

                Topics in Biology

                 Joshua Cannon

                  18 July 2009
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Abstract

Acute myeloid leukemia is formed from a collection of genetic and environmental sources which

correlate to the treatment options for a patient, making the disease seem almost paradoxical. This

cancer of the blood is very complex; causation and treatment come in a variety of forms. An experiment

was formed to simulate how radiation affected sublethal and lethal mutation in cancerous cells. Seratia

marcescens was used to represent the AML cells; UV rays symbolized radiation therapy. The end

conclusion was that as the amount of UV radiation increased, the amount of sublethal mutation

decreased and the amount of lethal mutation increased. This could then be applied to acute myeloid

leukemia cells. The irony of the situation is that the disease may have been caused by genetic mutations

of the oncogenes, yet mutation is used to correct the disorder. Acute myeloid leukemia is a somewhat

contradictory disease.
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                          Acute Myeloid Leukemia: A Paradoxical Phenomenon


        Cancer. The word itself is enough to cause panic and heartache, especially when the disease

strikes a loved one. The placement of the cancer is not the true issue, rather, it is the problem of coping

with a cancer, such as leukemia. Leukemia is a cancer of the bone marrow and blood (Leukemia, 2007).

Blood cells form in the bone marrow from stem cells, which make red blood cells, white blood cells, and

platelets. White blood cells fight infection; red blood cells carry oxygen to tissues; platelets form clots to

control bleeding (National Cancer Institute, 2008). Leukemia forms when the bone marrow makes

abnormal white blood cells, also known as leukocytes or WBC’s (Miller, 2007). Lack of normal white

blood cells creates a low red cell count, or anemia. As abnormal cells continue to grow in the bone

marrow, normal cells are crowded out, making an uncontrollable accumulation of abnormal cells

(Leukemia, 2007). This disease causes more deaths than any other childhood cancer and is the most

common type found in children (Kyle, 2001). There are four types of leukemia: acute myeloid, acute

lymphocytic, chronic myeloid and chronic lymphocytic. Lymphocytic leukemia occurs when the cell

transformation takes place in a type of marrow cell that creates lymphocytes. Myelogenous (myeloid)

leukemia occurs when the cell change takes place in a marrow cell that forms red cells and some white

blood cells (Leukemia, 2007). Ninety-eight percent of leukemia is classified as acute in children (Miller,

2007). Cancers of children under 20 years old were on the rise from 1990 to 2005 and will probably

continue to follow the growing trend (Figure 1).


        Acute myeloid leukemia (AML) is a disease that creates “nonfunctional” cells, which cannot do

the normal functions of a specific cell (Leukemia, 2007). AML is made of blast cells, also known as

myeloblasts, that can progress rapidly, creating an abundance of abnormal cells that cannot do any work

on normal white blood cells. This disease accounts for more than 13,000 leukemia cases each year

(National Cancer Institute, 2008). Acute myeloid leukemia is one of the most common types of cancers
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that children have to face. Thirty-eight percent of children with leukemia have AML (Miller, 2007). This

type of cancer is also mostly diagnosed in children less than one year old (Kyle, 2001). Acute myeloid

leukemia is formed from a collection of genetic and environmental sources which correlate to the

treatment options for a patient, making the disease seem almost paradoxical.


        Many environmental factors contribute to the growing cases of acute myeloid leukemia,

especially in reference to the medical field. Although no exact cause of leukemia is known, scientists

have investigated the issue and have found many outside factors that have a high correlation with AML.

Those who were in an atom bomb explosion or had prior radiation therapy have an increased risk of

obtaining AML (National Cancer Institute, 2008). If x-rays were obtained in the pre-natal or post-natal

period, this is considered a “known” cause of leukemia (Kyle, 2001). Diagnostic x-rays from dental scans

and CT scans are also correlated with AML. Cancer patients who were treated with chemotherapy

drugs, such as alkylating agents or topoisomerase inhibitors, are at a higher chance of getting acute

leukemia later in life (National Cancer Institute, 2008). Children receiving medical drugs to repress their

immune system after organ transplants are also considered to be in jeopardy of receiving acute myeloid

leukemia (Miller, 2007).


        Medical treatments are not the only link to leukemia; simple household items and common

elements can pose threat to helpless victims. Pesticide exposure to adults and children alike can result

in acute myeloid leukemia. “In a 1987 National Cancer Institute study, the risk of childhood leukemia

increased nearly four times when pesticides were used within the house at least once per week” (Kyle,

2001). Parents exposed to solvents, paints, benzene, or other motor vehicle related jobs can create an

unsafe environment for their children. If the father works with petroleum or lead, the child is at risk for

AML, as is if a mother works near metal dust, pigments, or paints (Kyle, 2001). Benzene, an element

found in the chemical industry, can cause AML when found in gasoline or smoke (National Cancer
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Institute, 2008). Electric magnetic fields (or EMFs) that are located near high-voltage areas can heighten

the chances of AML. One recent study found the following:


        The risk of leukemia was elevated when exposure to EMFs was consistent over the term of the

        pregnancy and in cases where the design of the water system in the home led to "ground

        currents" from connections between plumbing pipes and the grounding for the electricity.

        (Kyle, 2001)


Smoking cigarettes can not only increase one’s chance of receiving lung cancer, yet it can also create a

potential risk of AML (National Cancer Institute, 2008). These environmental factors weaken the

immune system, which opens the way for genetic disorders and mutations to form.


        When the environmental factors have played their role in the formation of leukemia, genetic

factors take a deadly toll. Almost all cancers begin as mutations in the genetic material, or DNA

(Swierzewski, 1999). These genetic mutations, or an alteration in normal genes, are acquired

throughout an individual’s lifetime (MedicineWorld, 2008). One or more white blood cells experience

DNA loss or damage; these errors are then copied and passed on (Swierzewski, 1999). Mutations are

grouped into two categories: translocation and deletion. Translocation occurs when two blood cell

chromosomes exchange genetic materials and deletion takes place when a chromosome loses genetic

material (MedicineWorld, 2008). Translocations create damage when one section of a chromosome is

displaced and attached to another, therefore interfering with the normal gene sequence. With such an

abnormality present, oncogenes, or genes that turn normal cells into cancerous tumor cells, may be

“switched on” to produce cancer (Swierzewski, 1999).


        Many diseases affect a person’s chances of obtaining acute myeloid leukemia. Li-Fraumeni

syndrome, Kleinfelter syndrome, neurofibromatosis, ataxia telangectasia, and Fanconi's anemia have
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been proven to increase a person’s risk of AML (Miller, 2007). Myelodysplastic syndrome and other

blood disorders heighten the chance of getting AML, considering leukemia is a blood-related cancer.

Down syndrome and other inherited diseases also increase one’s vulnerability of getting the disease,

since the immune system is already weakened and the chromosomes are open to abnormalities

(National Cancer Institute, 2008). Twins are also at high risk if one twin were diagnosed with the

disease. “Children have a 20% to 25% chance of developing ALL or AML if they have an identical twin

that was diagnosed with the illness before age 6” (Miller, 2007). Numerous disorders and genetic

factors contribute to the cause of acute myeloid leukemia.


        As these disorders appear, patients seek different types of treatment options, of which include

chemotherapy. The goal of all treatments is to destroy signs of leukemia and make the symptoms go

away through remission. Treatment depends on age and if the cancer was found in the cerebrospinal

fluid or not (National Cancer Institute, 2008). AML patients need immediate treatment; most start with

induction treatment, in which the majority of the cancer cells are destroyed. Induction chemotherapy

consists of a seven-day course of cytosar arabinoside and anthracycline. If the acute myeloid leukemia

is not entirely destroyed, consolidation or maintenance therapy is used. In this stage, minimal residual

disease left behind is attempted to be destroyed with high dose cytosar arabinoside or HDAC

(MedicineWorld, 2008). Chemotherapy can harm blood cells by making them less defensive; it also

harms cells in the hair and cells in the digestive tract (National Cancer Institute, 2008).


        Stem cell treatment is also a benefactor for those who undergo AML. Umbilical cord blood stem

cells or peripheral stem cells are two sources that greatly help a patient through treatment. The

different types of stem cells that can be used in treatments are autologous, allogeneic, and syngeneic

stem cells. The stem cell treatment is similar to a blood transfusion; after undergoing a regular
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treatment of chemotherapy, one has healthy cells pumped into his/her veins (National Cancer Institute,

2008).


         Although radiation through diagnostic x-rays can create acute myeloid leukemia, high-frequency

radiation treatments can cure the disease. Radiation therapy, also known as radiotherapy, uses high-

energy rays to kill leukemia cells (National Cancer Institute, 2008). “Irradiation” uses the same type of

radiation as that of diagnostic x-rays, but in elevated doses. Radiation therapy damages DNA within

cells, therefore preventing the growth and reproduction of cancerous cells. Healthy cells are at a

potential risk of being destroyed; however, physicians are careful when treating patient so as not to

endanger the patient. There are a variety of radiation treatments, but two are very common. External

Beam radiation is delivered by a linear accelerator or “linac”. Since this machine can deliver radiation

from different angles, the process decreases the chances of harming healthy cells.

Radioimmunotherapy occurs when radioactive molecules are attached to monoclonal antibodies to

target cancer cells (Radiation Therapy, 2008). Monoclonal antibodies (Mabs) eradicate cancerous cells

with toxins while sparing normal tissue (MedicineWorld, 2008). A single treatment of radiation lasts for

only a few minutes; however, a patient will have to wait in the treatment room for twenty to thirty

minutes. Side effects can include anything from fatigue to hair loss, creating psychological damage to a

patient (Radiation Therapy, 2008).


         An experiment was conducted to simulate how radiation affects the mutation of cancerous cells

in radiation therapy. The UV light represents radiation therapy; the seratia marcescens corresponds to

the acute myeloid leukemia cells. Two liquid cultures were made with seratia marcescens through

sterile technique. Sterile technique is the process by which a person tries to prevent the contamination

of cultures. An inoculated loop was flamed to prevent cross-contamination; the seratia marcescens

bacteria was then added to the liquid and stored for twenty-four hours at 25 degrees Celsius. The
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bacteria were then plated on nutrient agar plates using a bacterial spreader and exposed to ultraviolet

light, with exposure time being 0, 30, 60, 120, 180, 300, and 600 seconds (Figure 2). The plates were

then incubated for about 36 hours. The bacteria would be killed in the three, five, and ten minute

spectrum, but not in the other four trays. The reason behind this is that bacteria that are exposed to UV

light for long periods of time usually perish within a few minutes in radiotherapy. This could be applied

to the actions made by cancerous cells, such as acute myeloid leukemia.


        The results of the experiment were unexpected and astonishing. No plate was completely free

of bacteria; the ten minute plate had the minimum amount of growth (Figure 3). Sublethal mutation

occurs when the bacteria form a white mass on the plate, showing that the cells are changing their

structure. If there is no cell growth, the end result is classified as lethal mutation. The radiation began

as sublethal with exposure of 30 seconds (Figure 5). The ten minute, end result showed little to no

growth of bacteria, promising lethal mutation. The plates showed that as the amount of radiation

increased, the amount of sublethal mutation decreased while the amount of lethal mutation increased

(Figure 10). There is, however, an outlier in the data set. The sample taken for a time of 120 seconds

seemed to have increased its sublethal mutation, (Figure 7). This may be due to the fact that the

bacteria was trying to correct itself and prevent possible death. While looking at Figure 10, one might

conclude that mutation increased from 0 to 30 seconds; however, this is an incorrect statement. The

control plate would not have any sublethal mutation, so when interpreting the results, it is best to look

at the actual experimental data. There are some lurking variables that could have biased the study, such

as air exposure, not completely sterilizing the cultures, or not completely mixing the cultures to create

the preferred results. Bacteria in the air could have mutated the seratia marcescens, therefore

compromising the results. If the cultures were not mixed properly or were not sterilized properly, the

actual result could be astounding. The outcome of the seratia marcescens can be applied to cancerous
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cells, such as acute myeloid leukemia. When a patient undergoes radiation therapy, an individual

experiences sublethal mutation in the cancer cells, much like how the cancer started. As the radiation

increased to ten minutes, the sublethal mutations diminished and lethal mutations increased.

Therefore, an individual with acute myeloid leukemia is at an advantage when taking radiotherapy,

although ironically, radiation can be a leading cause in the formation of leukemia.


        As scientific research and inquiry bear witness, the genetic and environmental causes correlate

to the treatment options for a victim of acute myeloid leukemia. The environmental and genetic

sources of the disease are interrelated; one seems to generate the latter by causing a deficiency in the

immune system, therefore opening a way into genetic mutation. Many treatment options hope to

correct cancerous oncogenes with monoclonal antibodies, stem cells, or radiation therapy. It seems

almost paradoxical that the cause of acute myeloid leukemia can be linked to a cure. Medical tests such

as diagnostic x-rays can lead to AML; medical surgeries, such as bone marrow transplants, can cure the

cancer. Benzene and other chemicals mutate cells to produce cancer; chemotherapy and other drugs

treat the disorder. Atomic bomb radiation and radiation therapy can leave a family with a cancerous

diagnosis; radiotherapy such as external beam radiation can save a life. As expressed by Figure 1, acute

myeloid leukemia has been on the rise in young children for the past couple decades. Experiments

could be continued through analyzing the significance of environmental and genetic factors on the

treatment option and how the factors affect the amount of treatment needed. Although the true cause

of AML is not known, scientists are continuing their research to find a definitive reason and possibly a

cure for acute myeloid leukemia. It could be quite plausible that both answers lie in one element, and

the paradoxical enigma would finally be resolved.
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Figure 1; Cancer Incidence for Children Under 20 by Type




Figure 2; Bacteria exposed to ultraviolet rays
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                                   Figure 3; Results after 600 seconds




Figure 4; Results after 0 second Figure 5; Results after 30 second Figure 6; Results after 60 seconds




Figure 7;                               Figure 8;                        Figure 9;

Results after 120 seconds               Results after 180 seconds        Results after 300 seconds
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Figure 10; Amount of Sublethal Mutation Over 10 Minutes


                                                        Amount of Sublethal Mutation Over
                                                                   10 Minutes
   Amount of sublethal mutation in millions




                                              4.5
                                               4
                                              3.5
                                               3
                                              2.5
                                               2
                                              1.5
                                               1
                                              0.5
                                               0
                                                    0      30      60        120          180   300         600
                                                                        Time in Seconds
                                                              Acute Myeloid Leukemia              13


                                             Works Cited


Kyle, A. (2001). Children, Cancer, and the Environment: Leukemia. Retrieved June 29, 2009, from

       http://www.envirohealthpolicy.net/kidstest/cancer%20Pages/Individual%20Cancers/Leukemia.

       htm


Leukemia and Lymphoma Society. (2007). Leukemia. Retrieved June 29, 2009, from Leukemia and

       Lymphoma Society on the World Wide Web: http://www.leukemia-

       lymphoma.org/all_page?item_id=7026


Leukemia and Lymphoma Society. (2008). Radiation Therapy. Retrieved July 7, 2009, from Leukemia and

       Lymphoma Society on the World Wide Web: http://www.leukemia-

       lymphoma.org/all_page.adp?item_id=9083


MedicineWorld. (2008). Acute Myeloid Leukemia. Retrieved June 29, 2009, from

       http://medicineworld.org/cancer/hematological/leukemias/acute-mueloid-leukemia-aml.html


Miller, R. (2007). Childhood Cancer: Leukemia. Retrieved June 29, 2009, from

       http://kidshealth.org/parent/medical/cancer/cancer_leukemia.html


National Cancer Institute. (2008). What You Need to Know About Leukemia. Retrieved June 29, 2009,

       from U.S. National Institutes of Health on the World Wide Web:

       http://www.cancer.gov/cancertopics/wyntk/leukemia


Swierzewski, S. (1999). Leukemia: Leukemia causes. Retrieved June 29, 2009, from

       http://www.oncology.com/leukemias/causes.shtml


U.S. Environmental Protection Agency. (2008). Types of Childhood Cancers. Retrieved July 8, 2009, from

       http://images.google.com/imgres?imgurl=http://www.epa.gov/envirohealth/children/images/D
                                                   Acute Myeloid Leukemia            14


6ahighres.JPG&imgrefurl=http://www.epa.gov/envirohealth/children/child_illness/d6-

graph.htm

				
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