Adaline, Addy, was born on June 28, making her astrological sign Cancer, but little did anyone know the irony. A few days ago, the two-year old Addy was brought into her pediatrician’s office because she was displaying signs of an ear infection and fever. She was prescribed amoxicillin to fight the infection; however, 48 hours later, Addy had not improved. She complained of intermittent fevers, loss of appetite, and refused to stand. Also, her mother had recently taken Addy to the Zoo, one of Addy’s favorite places, but the toddler slept in her stroller the whole time. Not even her favorite animal exhibit, the giraffe, could keep her awake. Her mother brought Addy back to the pediatrician’s office with the suspicion that Addy was dealing with something greater than an ear infection.
During the appointment, the doctor was concerned that Addy wasn’t fighting off the ear infection even with the aid of antibiotics. Upon further examination the doctor notes that Addy is pale, has abdominal swelling and an extensive history of numerous persistent infections within the last year. These abnormalities in her health are consistent with a diagnosis concerned with a compromised immune system, so the doctor sends Addy and her mother to Oncology/Hematology department for a full blood work up and white blood cell differential. Results reveal a white blood cell count of 42,000 cells/microliter, hemoglobin of 7.6 g/dl and a platelet count of 87,000 platelets per microliter. In comparison, normal results for a 2-year-old child are white blood cell count of 6,000-17,000 cells per microliter, hemoglobin of 11.5-15.5 g/dl and a platelet count of 150,000-450,000 platelets per microliter[1] . In other words, Addy has an unusually high white blood cell count, combined with low platelet and red blood cell counts. If in the follow-up bone marrow aspiration test Addy has greater than twenty-five percent blasts (cells that are premature and have not decided what type of white blood cell they will be) in her bone marrow then she will be diagnosed with leukemia[2] . The marrow aspiration test shows that she has 98 percent blasts. To everyone’s dismay, little Addy has leukemia.

There are four main types of leukemia in children. Two types of leukemia, acute myelogenous leukemia and chronic myelogenous leukemia, arise from myeloid cells (cells that give rise to white blood cells, red blood cells, or platelets). The two forms mainly differ in that the later type is rare in children, has a very specific genetic mutation and a slow progression. The other two types of leukemia are acute lymphoblastic leukemia and chronic lymphoblastic leukemia. These two forms of leukemia arise from problems with a specific type of white blood cell called lymphocytes, which reside in the bone marrow. Chronic lymphocytic leukemia is very rare in children and grows slower than its acute form. To diagnose chronic lymphoblastic leukemia doctors conduct tests that look for low amounts of specific proteins called ZAP-70 and CD38[3] .

While the diagnosis is shocking, tests are promptly run to determine the type of leukemia to diagnosis Addy. First, the bone marrow aspiration test is sent for analysis to determine the type of cell (lymphocytes or myeloid) that is the source of mutation. The results show the mutation occurs in the lymphocytes and the build up of cells is rapidly progressing. This means that Addy has acute lymphoblastic leukemia (ALL). Addy has the form of leukemia that accounts for 60-65 percent of leukemia in children[4] . As stated previously, ALL is fast growing cancer cell growth of lymphoblast cells. It originates in the bone marrow, so it can quickly spread to all parts of the body. The white blood cells abnormally divide at rapid rates causing numerous downstream affects on the body. Upon further analysis, the specific type of lymphoblast cells (B or T-cell) that is mutated is evaluated. In Addy’s case it is her B-cells. These cells are diving rapidly and dividing at too early of maturity state to properly carryout their function, giving rise to her diagnosis[5] .

All the pieces of the puzzle fit together with this diagnosis. Many of Addy’s symptoms can be directly related to leukemic intrusion of the bone marrow. Addy’s unwillingness to stand indicates that she was experiencing joint and bone pain caused by the build up of leukemia cells at the surface of bones causing pressure in the bone marrow space[6] . This is common in 23% of new patients[7] . Secondly, the high white blood cell count indicates that red blood cells (RBCs) are being crowded out in the bone marrow. As a result, there is not enough RBCs and therefore hemoglobin to deliver oxygen to tissues in the body. Without oxygen, skin can appear pale and fatigue can occur. Additionally, since the toddler’s leukemia originates from B-cells, the cells responsible for secreting antibodies to fight viral and bacterial infection, she will be more prone to infection and have trouble fighting off infections[8] . Loss of appetite in ALL is often caused by swelling in the stomach region can be a result of white blood cells building up in the spleen or liver and decreasing the space her stomach can expand with food[9] .

The 5-year survival rate is more than 85 percent for children diagnosed with ALL[10] . Unfortunately, Addy is a high-risk patient because her lumbar puncture test shows blasts in the central nervous system, CNS, and other tests reveal blasts in the liver and spleen. She is also considered a high-risk patient because her white blood cell count is greater than 50,000 cells per microliter; a number that serves as a threshold for more advanced cancer[11] . Luckily, early pre B-cell ALL has a higher cure rate than other subtypes of ALL and children in her age range have a better cure rate[12] . Yet, due her high-risk factors, she will have to undergo more intense treatment.
Addy's parents are in shock at the diagnosis. Just a few weeks ago Addy had so much energy ran to the stuffed animal sec ion of Toys R Us, grabbed every stuffed giraffe she could find and rand around with them in her arms until her mom finally caught up with her. She has always been such a vivacious child; how could this happen to their little girl?

Doctors explain that ALL is a heterogeneous disease, which means that it is caused by many differences in allelic mutations versus one allele causing several different phenotypes. Addy underwent genomic testing to find out what her unique genomic aberrations are and to better understand the molecular basis for targeted treatment.

Her genomic results have come back and her doctors meet with Addy's parents to explain that there are two important categories of gene function to understand the molecular basis of cancer. The first is oncogenes, which are responsible for growth, division and evading cell death. Oncogenes can cause cancer by uncontrolled cell growth or creating immortal cancer cells that the body would normally rid. For example, after Addy’s genetic analysis doctors discovered that she has a mutation in her ras gene. Ras is responsible for signal transduction by passing signals along inside the cell. Specifically for Addy, the N-ras gene has a point mutation, which has made it into an oncogene for her cancer. According to a study by Dr. Martin J. Cline[13] , this genetic alteration is common in 14 percent of patients with ALL. Another family of genes with chromosomal aberrations typically found in ALL is called tumor suppressor genes. The two important proteins involved in tumor suppressor genes for Addy’s disease are p53 and RB1. DNA mutations that turn on or off tumor suppressors like p53 and RB can cause cancer because they allow extra growth of cells. p53 is found mutated in more than 50 percent of human cancer[14] . Addy is no exception to this statistic; however, while this mutation is common in cancer in general, it is rare in her disease as it is only found in two percent of pre-B cell ALL.

While this seems like a simple answer to Addy’s predicament, development of ALL involves many factors and is a multi-step process. These mutations in her genome do not necessarily lead to ALL for all patients, especially if the gene is only mutated in one copy of the gene. The p53 and ras genes must have two mutated copies of the gene to even pose an issue. Plus, there are many small genomic and environmental factors that add up to create cancer. It is hard to identify all of them; yet, it is likely that the activation of her oncogene, N-ras, and the loss of function of the tumor suppressors, p53 and RB1, combined with other minor abnormal circumstances resulted in cancer by allowing uncontrollable proliferation and not suppressing tumor growth.
Doctors describe more specifically the role of tumor suppressor genes in Addy’s leukemia. They explain that P53 and RB1 work together to negatively regulate cell division through tumor suppressor genes. RB1 is vital to the formation of blood cells because when the body is functioning normally, RB1 reads signals from outside and inside the cell and acts between the G1 and S phase of the cell cycle to decide if the cell should progressthrough mitosis to create more cells. In little Addy, the loss of RB1 means that she does not have a monitor of the cell cycle and that is why her cells keep making too many clones. This is a fairly common occurrence as abnormalities in RB1 occur in ten to thirty percent of all types of acute leukemia. Additionally, abnormalities in p53 contribute to Addy’s leukemia. The role of p53 is to halt the cell from progressing into division if p53 senses genomic damage or lack of cell nutrients. In normal cells, this allows the cell to fix its DNA or gather more building blocks to have successful cloning. However, a genomic error in p53 can have large consequences to the regulation of cell division because the genomic errors that would normally be fixed before the cell proliferates are not fixed.

As the doctors explained to Addy’s parents, the other major contributor to Addy’s leukemia is the N-ras gene. N-Ras is involved in a pathway called the Ras/Raf/MEK/ERK pathway (abbreviated Ras pathway). The Ras pathway is made of a chain of proteins that pass along a signal from a receptor at the cell surface to the DNA in the nucleus of the cell. It begins with a signaling molecule outside the cell and ends with the expression of a protein or a change in the cell. These changes are an array of cellular functions including: cell proliferation, survival, differentiation, angiogenesis and migration. While the Ras/Raf/MEK/ERK pathway is a daunting name, each word in the pathway corresponds to a major step in the pathway.
The pathway begins by a small protein that encourages cell division or mitosis, called a mitogen, binding to a protein called tyrosine kinase (RTK) like a lock and key at the cell surface. The mitogen is the message that needs to be passed on and communicated to the DNA of the cell through the pathway. This pathway is characterized by the addition of a phosphate group to the next neighboring protein, which propagates the signal down the pathway to the end result like falling dominos. So, once RTK is bound to the mitogen, it stimulates the autophosphorolyation of GDP to GTP on ras (see Figure1
k.png
Figure 1: Regulation of Ras Activity
[15] ), which acts as an “on/”off” switch. Adding a phosphate group to the next protein turns it “on” and taking off the phosphate group turns it “off.” When ras is in the “on” position the signal from outside the cell is communicated to the nucleus of the cell until the final outcome is a protein or change in the cell. Now that Ras is “on” it adds a phosphate group to Raf, the next word in the name of the pathway. Then, MEK is phosphorylated and receives the signal until finally ERK receives the signal. Once ERK receives the signal, the message can be fully translated in the nucleus to create a change in the cell.

In Addy’s case, the ras pathway that uses the N-ras has been mutated. In the largest study about this to date, ninety percent of N-ras mutations showed a point mutation switch of guanine to adenosine and have been shown to reduce the de-phosphorylation of GTP to GDP by inhibiting GAP[16] . This means that N-ras can only be bound to GTP leaving this pathway stuck “on” and continually promoting cell division. This explains the uncontrollable cell growth and formation of leukemia.

Addy’s doctors explain that in the future patients with similar genetic aberrations to Addy may benefit from targeting the Ras pathway directly because it would target leukemia cells specifically instead of having systemic effects from more general chemotherapies. This pathway has many components, which lead to the potential for therapeutic targeting. The proteins that are most commonly mutated and can be targeted for therapy are colored red in Figure 2[17]
k2.png
Figure 2: Ras Pathway
. Interestingly, this pathway is commonly found in over 80 percent of all cutaneous melanomas and BRAF targeted therapies include Vemurafenib and dabrafenib show impressive results in systemic therapy for melanoma with BRAF mutations[18] . This finding may be applied to ALL patients in the future to more directly combat the molecular problems creating ALL in Addy. For example, Memorial Sloan Kettering Cancer Center is starting a trial on Vemurafenib, a BRAF inhibitor, in Patients with Hairy Cell Leukemia[19] . While Hairy Cell Leukemia is not acute lymphoblatic leukemia, it is a disease stemming from the blood so the findings of this study will provide more evidence than the finding from the melanoma Vemurafenib trials as to whether the ras pathway can be directly targeted in the future to treat patients with ALL and BRAF mutations. Vemurafenib is a small molecule inhibitor of BRAF that would help reduce the frequency of cell division in cancerous cells[20] . Trials like this give Addy’s parents hope that similar to the BRAF drug, a specific N-Ras drug can be found to help treat ALL so that there are more drug treatment options in the terrible circumstance that Addy’s leukemia comes back in the future. For now, she will most likely have to undergo the standard ALL treatment, which will control for proliferative growth and lack of tumor suppression in the other indirect ways that are still shown to be effective.

At Children’s Hospital Colorado, one of the top pediatric cancer treatment centers in America, her doctor assesses the biology and progression of her cancer and recommends that she begin prompt chemotherapy treatment. At this time, the doctor does not see a need for experimental treatment. Standard treatments are found to have exemplary survival rates. The standard treatment will be the foundation of Addy’s treatment, but because she is a high-risk patient, she will she will have to receive a treatment slightly tailored to her needs. This may include stem cell transplant, surgery, or radiation therapy.

Currently, her treatment will be comprised of the standard treatment, the addition of specific drugs and higher dosages of certain drugs. This is because high-risk children are shown to respond to better to these adjustments. For example, in the CCG-1882 trial, they increased the dose of methotrexate and added vincristine and L-asparaginase to the maintenance period of the standard treatment[21] . Proving that escalating the dosages and/or frequency of drugs compared to the standard significantly increases the event-free-survival rate. The doctors explain to Addy’s parents that despite research, they do not know the molecular basis of this outcome. However, they do know that current research shows that standard treatment with slight modifications to the individual’s disease has shown to have five-year survival rates of more than 85 percent[22] .
Moreover, chemotherapy “is treatment with anti-cancer drugs that are given into a vein, into a muscle, into the cerebrospinal fluid, or taken as pills[23] .” Drugs are specifically combined to target cancerous cells entering the bloodstream and invade all areas of the body. In a broad sense, chemotherapy works by killing cells that grow and divide faster than normal cells. Each drug does this in its own way. However, treatment can damage normal cells too, especially in children when organs are still developing. Normal cell division can be similar to that of abnormal cancer growth and organs can accidently be attacked by chemo. Over the next two to three years, she will receive intense periods of chemotherapy followed by rest periods to let her body recover. Chemotherapy is divided into three stages: induction, consolidation, and maintenance.

The goal in the induction phase is to kill 99.9 percent of Addy’s nearly one hundred billion leukemia cells within the first month of treatment[24] . If treatment is successful, then Addy will reach remission after just one month of treatment. Remission is when there are no more leukemia cells found in bone marrow, normal cells begin to populate and blood counts return to normal. Addy’s doctor is optimistic for this outcome because it occurs in ninety-five percent of children with ALL[25] . Through frequent prolonged hospital stays, Addy will start a chemotherapy drug mix of L-asparaginase, vincristine, dexamethasone, and daunorubicin. She will receive the drugs intravenously and via the cerebral spinal fluid (also called intrathecal chemotherapy). Intrathecal chemotherapy is administered through a spinal tap and designed to kill the leukemia cells that spread to her brain and spinal cord. Little Addy will receive her initial chemotherapy regimen three times throughout the first month of treatment[26] .

When these drugs are effective, each inhibit a part of the replication of cells. As a result, the amount of lymphoblast cells in the body decreases and helps to rid Addy of cancer. For example, L-asparaginase is a hydrolase that breaks up the amino acid, L-asparagine, which is essential in the function of lymphoblast cells[27] . When L-asparagine is broken up, levels of asparagine drop in the body and this inhibits RNA and DNA synthesis in cells[28] . In turn, most lymphoblastic cells will undergo apoptosis, freeing Addy’s body of the abnormal lymphoblast cells. This drug is highly effective, as ninety percent of patients treated with this drug have been shown to enter complete remission[29] . Secondly, dexamethasone is a steroid, which is a hormone-like drug similar to that released from the adrenal gland. It is used in Addy’s therapy to try to prevent allergic reactions, nausea and vomiting during her chemo treatment. Danuorubicin belongs to a category of drug called Anthracycline, which are called, “anti-tumor antibiotics[30] .” However, these are not antibiotics in the traditional sense that one might receive when they have strep throat. These antibiotics interfere with enzymes related to the replication of DNA and modify DNA in cancer cells to keep them from dividing and growing. Vincristine is a mitotic inhibitor drug that arrests mitosis in the M phase of the cell cycle. It damages cells by keeping enzymes from making proteins needed for cell reproduction. It does this by irreversibly binding to tubulin, which messes up the microtubule assemble/disassembly process. Ultimately, this leads to the halt of the cell cycle in metaphase[31] .
After a month of treatment, Addy is responding well to the chemotherapy. She has entered remission. There are still about 100 million leukemia cells left in the body, so Addy begins the consolidation phase of chemo for the next few months[32] . Addy will receive a new mixture of drugs in effort to reduce the development of chemotherapy resistance by the remaining leukemia cells. The drugs that she will be given are methotrexate, 6-mercaptopurine, and doxorubicin. She will receive this mix of drugs four to six more times throughout the next month or two. The frequency will dwindle through the course of her treatment.

This round of drugs helps purge leukemia by disrupting the formation of nucleotide bases in the synthesis of RNA and DNA. Therefore, the leukemia cells cannot reproduce, which increases Addy’s chance of staying in remission. For example, methotrexate binds to and inhibits an enzyme called dihydrofolate reducatse. This inhibits DNA and RNA synthesis by interfering with purine synthesis, which is essential to building the nucleotide bases in DNA and RNA. It also inhibits the synthesis of a fundamental nucleotide in thymine. 6-mercaptopurine inhibits the formation of purine nucleotides. This in turn, prevents DNA synthesis. Doxorubicin, is an anthracycline antibiotic and works similarly to that of daunorubicin. Doxorubicin inserts itself between base pairs in the DNA helix and prohibits DNA replication. Further, doxorubicin forms oxygen free radicals, which create a toxic environment for cells causing them to apoptosis.

The progression of leukemia cells into Addy’s central nervous system is worrisome, so the doctor provides two treatment options for her parents to choose from. First, the doctor provides brain radiation as an option because this is the most common course of treatment today. Radiation therapy is high-energy rays targeted to kill and shrink cancer cells. Like chemotherapy, radiation therapy can affect normal cells too causing side effects, which is why it is typically avoided for children under five. The brain is still undergoing fundamental development until five years old so brain radiation can have many cognitive effects. The second option the doctor presents is a clinical trial. In the clinical trial, Addy will not receive radiation therapy, but instead receive intrathecal chemotherapy and high-dose methotrexatel. The doctors recommend the clinical trial because of Addy’s age; she is only two years old. While there is no guarantee that the clinical trial will have an effect similar to that of brain radiation, which has been proven to have a high survival rate, the cognitive effects that brain radiation may have at her age is extensive. If her parents chose radiation, Addy may experience learning difficulties and disabilities because her brain is still developing. These cognitive impairments include: lower IQ scores, lower test scores, memory and attention problems, poor hand-eye coordination, and/or behavioral problems. All parts of the brain will be affected, but non-verbal skills, like math, are more sensitive than others. If Addy was a year or two older the doctors may not suggest this because the risk of a learning deficit is favorable to that of death; however, at her age a clinical trial is worth the risk. Additionally, the doctors reason that this clinical trial is ethical because they have two categories of treatment. They have a category for low risk patients and one for high-risk patients. Addy will be able to receive intense chemotherapy as she would if she did not participate in the study.

Despite doctors' recommendation to enter the clinical trial, Addy's parents do not want to take a chance with her recovery and opt for the standard treatment of care. She begins the maintenance cycle of chemotherapy treatment. Addy is sent home and instructed to continue to take a daily pill of 6-mercaptopurine and weekly methotrexate. Methotrexate has similar molecular basis as mercaptopurine. This treatment represents a basic and normal chemo regimen for children; however, since her leukemia is of higher risk doctors suggest adding vincristine and dexamethasone. Vincristine is given intravenously and a dexamethasone as a steroid every four to eight weeks[33] . There is no concrete data supporting how frequent these drugs are administered to Addy. There is a hint of evidence in trials like the CCG-1882 trial. In this trial, it was shown that in patients aged ten to twenty-one and endured an alternate-week of dosing showed a lower rate of osteonecrosis as a side effect. This same finding may be applicable to younger children and could explain why this dosing occurs.

Everyone is ecstatic that Addy is free of leukemia, but she will still be in danger of long-term side effects from her cancer treatment. Risks associated with ALL include: hearing loss, higher risk for heart disease, stroke and secondary cancers, as well as fertility, heart, lung, sexual development, learning, psychological and emotional problems[34] . While these risks are frightening, the current cancer is life threatening and treatment must occur. Additionally, osteoporosis or other bone damage may arise from steroid drugs and other chemo drugs. For example, treatment including presdinone or dexamethasone can cause osteonecrosis, which is when the blood vessels feeding the bones are damaged causing some bones to weaken or die from a lack of nutrients. Addy may experience broken bones or bone pain. Chemo may also contribute to a slower growth rate because of the direct effect radiation has on the growth of bone. As a result of treatment, growth and development can also be stunted by damage to the pituitary gland. The pituitary gland is the main gland of the endocrine system, which is responsible for important functions in growth and puberty by the release of hormones.

Addy’s parents must pay careful attention to signs of a second development of leukemia because remission is not a cure. For several years Addy will have to continue getting physical exams, lab tests and imagining tests to monitor her status. For instance, routine blood work is vital to maintaining Addy’s health because the doctors need to check the number of neutrophils in the body. If there is less than five percent neutrophil cell count in her body then the chemotherapy is killing too many of the bone marrow cells. This increases Addy’s chance of getting an infection. If the number of neutrophils makes up more than eleven percent of her total number of white blood cells then the chemotherapy is not killing enough hidden leukemia cells and needs to be adjusted. If these precautions are taken it is unusual for the cancer to come back after two years of remission.

At two years old, Addy has proved to be a strong little girl in her ongoing two-year treatment and defeat of her high-risk childhood Acute Lymphoblastic pre B-cell Leukemia. In fact, if you met Addy, you probably would never know the intense treatment she been through. When Addy comes in for check-ups she proudly shows off her stuffed giraffe to all the doctors and with her big brown eyes she beams about how she got to feed the giraffes at her recent visit to the Zoo.

She is quite the social butterfly, which is a relief as Addy’s diagnosis was her parent’s worst nightmare. Even with a high 85 percent chance of a five-year survival outcome, one always has to worry about chance that she could be in the 15 percent of children who are not able to defeat cancer. In order to minimize the risk of being in that 15 percent, Addy’s parents took the time to understand her cancer to make informed decisions about her treatment. They learned that her cancer developed from mutations in RB1, p53 and N-ras, which led to uncontrollable leukemic cell proliferation and inept tumor suppressor genes. While it was devastating for her parents to hear that currently there is no specific target for these genes and proteins, they were ecstatic that standard treatment was able to purge the leukemic cells in Addy’s body. Initially, doctors were disappointed that Addy’s parents chose not to enroll Addy in the clinical trial that would avoid brain radiation, but her parents made the most informed decision they could. Only time will tell how compromised her cognitive abilities will be from this choice.

Her recovery is a blessing. And, while it is ironic that her astrological sign is Cancer, this lucky girl will get to enjoy many more birthdays, in the medical sense of the word, cancer free!

Aperçu: It is amazing to see how resilient a small child can be to nearly 100 billion of her own toxic leukemia cells. We hope that she will continue to carry resiliency in all her challenges and future endeavors.

  1. ^ "Clinics and Departments." Children's Hospitals and Clinics of Minnesota. Children's Hospital, n.d. Web. 17 Apr. 2015. <http://www.childrensmn.org/manuals/lab/hematology/018981.asp>.
  2. ^ Stromer, Karen. "Pediatric Clips." The Children's Medical Center of Dayton 3 (2006): n. pag. Dayton Children's. Web. 6 Apr. 2015. <http://www.childrensdayton.org/cms/resource_library/pediatric_clips/5f8805104b541827/diagnosing_luekemia_in_children_2006.pdf>.
  3. ^ "Childhood Leukemia." The American Cancer Society. The American Cancer Society, 03 Feb. 2014. Web. 10 Apr. 2015. <http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood>.
  4. ^ Ibid.
  5. ^ Ibid.
  6. ^ Diseases & Conditions." Cleveland Clinic. The Cleveland Clinic Foundation, 22 Aug. 2013. Web. 10 Apr. 2015. <http://my.clevelandclinic.org/health/diseases_conditions/hic_Leukemia>.
  7. ^ Stromer, Karen. "Pediatric Clips." The Children's Medical Center of Dayton 3 (2006): n. pag. Dayton Children's. Web. 6 Apr. 2015. <http://www.childrensdayton.org/cms/resource_library/pediatric_clips/5f8805104b541827/diagnosing_luekemia_in_children_2006.pdf>.
  8. ^ Diseases & Conditions." Cleveland Clinic. The Cleveland Clinic Foundation, 22 Aug. 2013. Web. 10 Apr. 2015. <http://my.clevelandclinic.org/health/diseases_conditions/hic_Leukemia>.
  9. ^ "Childhood Leukemia." The American Cancer Society. The American Cancer Society, 03 Feb. 2014. Web. 10 Apr. 2015. <http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood>.
  10. ^ Ibid.
  11. ^ Ibid.
  12. ^ Ibid.
  13. ^ Cline, M. J. (1994). The molecular basis of leukemia. New England Journal of Medicine, 330(5), 328-336.
    <http://www.nejm.org/doi/full/10.1056/NEJM199402033300507>.
  14. ^ Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 24.5, Mutations Affecting Genome Stability. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21551/
  15. ^ Knight, Thomas, and Julie Anne Elizabeth Irving. "Ras/Raf/MEK/ERK Pathway Activation in Childhood Acute Lymphoblastic Leukemia and Its Therapeutic Targeting." Frontiers in Oncology. Frontiers Media S.A., n.d. Web. 15 May 2015. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067595/>.
  16. ^ Ibid.
  17. ^ Ibid.
  18. ^ Dr. Park, Jae H. "BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia." ClinicalTrials.gov. A Service of the U.S. National Institutes of Health, May 2015. Web. 26 May 2015. <https://clinicaltrials.gov/ct2/show/NCT01711632>.
  19. ^ Ibid.
  20. ^ "Definition of Vemurafenib." National Cancer Institute Drug Dictionary. National Cancer Institute, n.d. Web. 26 May 2015. <http://www.cancer.gov/publications/dictionaries/cancer-drug?CdrID=528954>.
  21. ^ "Childhood Acute Lymphoblastic Leukemia Treatment." National Cancer Institute. The National Institutes of Health, n.d. Web. 01 May 2015. <http://www.cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional/page5>.
  22. ^ "Childhood Leukemia." The American Cancer Society. The American Cancer Society, 03 Feb. 2014. Web. 10 Apr. 2015. <http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood>.
  23. ^ "Chemotherapy for Childhood Leukemia." Chemotherapy for Childhood Leukemia. American Cancer Society, 17 Apr. 2015. Web. 30 Apr. 2015. <http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood-leukemia-treating-chemotherapy>.
  24. ^ "Treatment of Children with Acute Lymphocytic Leukemia (ALL)." Treatment of Children with Acute Lymphocytic Leukemia (ALL). American Cancer Society, 17 Apr. 2015. Web. 30 Apr. 2015. <http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood-leukemia-treating-children-with-all>.
  25. ^ Ibid.
  26. ^ Ibid.
  27. ^ Piatkowska-Jakubas, B. "Use of L-asparaginase in Acute Lymphoblastic Leukemia: Recommendations of the Polish Adult Leukemia Group." (n.d.): n. pag. PubMed. Web. 24 Apr. 2015. <http://www.ncbi.nlm.nih.gov/pubmed/19140571>.
  28. ^ Ibid.
  29. ^ Ibid.
  30. ^ "Types of Chemotherapy Drugs." Types of Chemotherapy Drugs. American Cancer Society, 6 Feb. 2015. Web. 23 Apr. 2015. <http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/chemotherapy-principles-types-of-chemo-drugs>.
  31. ^ "Liposomal Vincristine Sulfate." National Cancer Institute. National Institutes of Health, n.d. Web. 23 Apr. 2015. <http://www.cancer.gov/drugdictionary?CdrID=38100>.
  32. ^ "Treatment of Children with Acute Lymphocytic Leukemia (ALL)." Treatment of Children with Acute Lymphocytic Leukemia (ALL). American Cancer Society, 17 Apr. 2015. Web. 30 Apr. 2015. <http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood-leukemia-treating-children-with-all>.
  33. ^ Ibid.
  34. ^ Ibid.