Lawrence+Santos

//** Gold Blooded **// Life always seems to find itself balancing between the good and bad. For every pleasure, some pain must come about, and when happiness enters our lives, grief follows right behind it. Take a man who founded a clothing brand based in San Francisco. With the utmost loyalty from locals and a work ethic like no other, he is able to continue running an extremely successful business for nearly 23 years. You may see some of his familiar designs on T-shirts that read “Gold Blooded” or a billboard right in front of Oracle Arena with his brand on it. This man, Evan Lessler, is the CEO and founder of Adapt Clothing. For the first 33 years of his life, everything seemed to be going as planned. Starting his career off as a visual designer for companies such as Apple and CNET Networks, Evan built upon his skills by adding entrepreneurship to arrive where he is today. But as we commonly see, the world finds a way to balance itself out. For Evan Lessler, that counterbalance to his success unfortunately came in the form of a sudden cancer, more specifically acute lymphoblastic leukemia. After years of hard work and dedication to his craft, no one, not even friends and family, expected Evan to develop such a serious disease.

Evan and the company had their biggest year in 2015, and with huge plans for 2016; the brand was set to surpass any goal that Evan had ever set. Evan and the company had huge plans for the New Year, until he began to develop flu-like symptoms. As hard as he works, Evan surprisingly rarely gets sick, so he took his symptoms as a common, seasonal flu. That assumption was one that he would come to regret. In early 2016, Evan noticed that he would become more fatigued from the normal workday. It became difficult for him to develop new content for his brand, and patrons may have noticed a manifestation of this through the slight slow-down in the production of merchandise. A visit to the doctor’s office in January 2016 revealed that Evan had developed Acute Lymphoblastic Leukemia (ALL), which is a type of aggressive blood cancer. As far as doctors could say, it had no explanation for developing — it was simply a cell mutation that could happen to anybody.

Acute lymphoblastic leukemia is type of cancer that is most commonly found in young children and the elderly, who account for 60% of all cases. The risk for the disease is highest at ages 5 and younger, and then the risk “declines slowly until the mid-20s, and begins to rise again slowly after age 50.” However, there are several subtypes of ALL that account for its development in certain age groups. “Pre (precursor) B cell ALL is the most common type in adults, mature B cell ALL is identified by particular genetic changes, and pre (precursor) T cell ALL is more likely to affect young adults and is more common in men.” A common symptom of ALL is a developing or weakened immune system, which may explain the prevalence in the disease amongst children and the elderly. ALL is also an acute form of leukemia, which entails rapid progression.

The disease develops when the DNA of a developing stem cell in the bone marrow is damaged, otherwise known as an acquired mutation. This damaged, immature cell goes on to develop into a lymphocyte cell, which then divides and multiplies to mature into leukemic lymphoblasts. The lymphoblasts, which are abnormal white blood cells and block the production of normal cells, grow and are sustained better than the normal cells. Consequently, healthy red blood cell counts drop below normal, which may have been a factor in Evan’s fatigue as he was living with poor oxygenation in his muscles. As with many forms of cancer, going just a few months without treatment can be fatal. Children who are treated with ALL demonstrate a more promising remission rate at about 98%, and although about 80% of adults will have remission, half of those patients will undergo relapse, ultimately resulting in only a 40% cure rate. Some risk factors include carrying inherited Down syndrome genes, being white, and exposure to radiation and other harmful chemicals ; all of which do not apply to Evan. With no family members developing any form of cancer and practicing a healthy lifestyle as a non-smoker, Evan’s case becomes that much more unusual. The very next month, Evan was immediately hospitalized, and since then, Evan has been working towards recovery.

Despite fighting through this endeavor, Evan still continues to run his business. Though production and his creative designs slow as he struggles with leukemia, he gains a sense of resiliency that motivates him to continue battling. Just because leukemia has drained much of his energy, it does not mean that Evan stops working. Evan has already opened up 5 stores and looks to extend his business outside of the Bay Area. Aware of the difficulty of coping with cancer and knowing that he can use his widespread influence to do his part in helping find a permanent cure for cancer. Evan recently released a T-shirt design that reads “Research and Destroy”, in which he donates 100% of the sales to the American Cancer Society. Now, all Evan can do is hope that this small “movement” can be valuable in the world of cancer.

//**Molecular Basis of Acute Lymhpoblastic Leukemia**//

What is it about Acute Lymphoblastic Leukemia that caused Evan to completely slow down production for his company? As we move to the molecular basis of ALL, we observe “plenty of novel copy number alterations (CNAs) and mutations that typically affect genes involved in lymphoid differentiation, proliferation, cell cycle, and transcription in BCP-ALL.” If we recall, more than 60% of ALL cases affect young children, however Evan developed the disease in his late 20’s. As patients increase in age, they are more likely to be diagnosed with B-cell precursor ALL as opposed to the child-prevalent T-cell variation. Evan’s development of BCP-ALL at an older age allows us narrow down which genes are likely affected, which, in Evan’s case is the trans-located BCR-ABL1 fusion gene.

Nearly every form of cancer relies on the characteristic of genome instability. Genomic instability is “a state giving rise to alterations or aberrations in the genetic material of an organism that alters its informational or structural integrity.” Acute lymphoblastic leukemia takes full advantage of this enabling characteristic. Although “ALL genomes typically harbor fewer structural alterations than many solid tumors, more than 50 recurring deletions or amplifications have been identified, many of which involve a single gene or few genes.” Some alterations in genetic material are chromosomal aberrations, which include copy number alterations. CNAs in ALL are observed in recurrent mutations in genes that control the development of lymphoids.

Being that genomic instability can drive the malignancy of ALL, it allows the cancer to display several hallmarks, especially in sustaining proliferative cell growth signaling and evading growth suppressors. In adult acute lymphoblastic leukemia, the BCR-ABL1 fusion gene is most commonly affected. The gene (see Figure 3) is formed when “pieces of chromosomes 9 and 22 break off and trade places. The ABL gene from chromosome 9 joins to the BCR gene on chromosome 22.” The genes affected by this translocation include PAX5, EBF1, and IKZF1. In order for a cell to proliferate or increase in cell number, it must receive some form of extracellular signal to communicate a cellular response. PAX5 encodes a transcription factor that helps control the normal formation of blood cells. Translocations affect PAX5 in a way that “accelerate[s] the development of B-cell precursor leukemia.” A loss of function in this gene indicates a tumor suppressor in which the diploid organism only has one functional copy and does not produce sufficient gene products; a term we can describe as haplo-insufficiency. EBF1 works in conjunction with PAX5, in that one of the transcription factors that EBF1 codes for includes the PAX5 gene. The haplo-insufficiency of either of genes contributes to the rapid progression of ALL. The most recurrent mutation occurs in the IKZF1 gene, which encodes for transcription factors needed for the development of all lymphoid types, including the immature lymphocytes that will eventually lead to leukemic lymphoblasts.

In the development of ALL, “it is likely that chromosomal rearrangements are acquired early… and drive transcriptional and epigenetic dysregulation and aberrant self-renewal. (See figure 4)” These genetic alterations result in the translocation of BCR-ABL1, which leads to “aberrant cytokine receptor and kinase signaling.” The two events together give rise to “the proliferation and establishment of the leukemic clone." These leukemic clones possess what is called a selective advantage, which results “in the fully malignant phenotype” of acute lymphoblastic leukemia.

The affected cytokine receptor and kinase signaling in ALL, as mentioned above, are associated with the JAK-STAT pathway and MAPK/ERK pathway, respectively. The JAK-STAT pathway “mediates signaling from cytokine, chemokine, and growth factor receptors via the JAK non-receptor tyrosine kinases and the STAT family of transcription factors.” The mutations found in JAK are mostly missense mutations and associated with the deletion of IKZF1. When STAT (signal transducer and activator of transcription) is phosphorylated, the MAPK/ERK pathway will then be activated as result. If tyrosine kinases are overexpressed, hyper-hematopoiesis and “constitutive activation by mutations” can occur that will eventually give rise to abnormally growing leukemic cells.” In other words, the signaling of the RAS protein will then be upregulated and result in uncontrolled growth and multiplication of cells.

Now that we know the molecular basis of acute lymphoblastic leukemia, the next step is treatment. What pathways or genes can we target in order to achieve the best state for Evan? Is it possible to treat Evan’s cancer, and if so, how long will Evan be in remission? As a man with ALL at the age of 30, the risk of relapse is even greater, but by knowing the affected genes, it allows us to consider a more specified type of treatment for Evan, whether that is through surgical, radiation, or medical oncology.

//**Treatment of Acute Lymphoblastic Leukemia**//

As cancer continues to dominate the war, we can only hope that there is some way to help the body fight and hold off the merciless disease. Cancer seeks to build an empire, spreading out and taking over in as many parts of the body it can reach. Thankfully for Evan, several systemic therapy options are available to give him the hope of extending his life.

In the diagnosis of acute lymphoblastic leukemia, the state of the Philadelphia chromosome is the primary indicator of the disease. If we recall from the molecular basis of ALL, the Philadelphia chromosome is the abnormal chromosome 22 in which a piece of chromosome 9 is translocated over (See Figure 1). When a patient is found to have Philadelphia chromosome-positive ALL, he or she will most likely receive a treatment combination of tyrosine kinase inhibitors and chemotherapy. Because tyrosine kinase inhibitors prevent self-dimerization and phosphorylation, they can counteract cancer cells’ ability to sustain proliferative growth. Along with TKI’s, chemotherapy can eradicate any cancerous cells by way of apoptosis induction. Several procedures such as blood, bone marrow, and chromosome tests are used to detect and diagnose acute lymphoblastic leukemia. Because Evan was found to have a mutation in the BCR-ABL1 fusion gene, targeted therapies can be narrowed down. Once thorough screening has been performed and the diagnosis has been given, a plan for treatment can be laid out.

Treatment for ALL typically involves “3 phases: induction (or remission induction), consolidation (intensification), [and] maintenance”. Induction chemotherapy aims for remission. This first step involves the use of drug therapy. Though a multitude of drugs may be used, “a targeted drug such as Imatinib (Gleevec)” shows to be the most effective in treating patients who are Philadelphia chromosome-positive. Referring back to the molecular basis of the disease, BCR-ABL1 is the mutated fusion gene that is found in patients with ALL. While other tyrosine kinase inhibitors can help treat Philadelphia chromosome-positive ALL, they do not match Imatinib’s capabilities. Imatinib specifically inhibits the tyrosine kinase controlling the BCR-ABL1 pathway that gave rise to Evan’s disease. By suppressing BCR-ABL1 tyrosine kinase, a down-regulation of the mutated PAX5, EBF1, and IKZF1 genes in ALL will result, thus inhibiting cancerous cells from sustaining proliferative growth.

When cancer begins to metastasize, it can produce fatal outcomes. ALL is no different, so a significant part in the treatment process involves central nervous system (CNS) prophylaxis; a form of chemotherapy that targets the central nervous system in order to kill any cancer cells that are present in the brain and spinal cord. The chemotherapy drug is “injected directly into the spinal fluid” (intrathecal chemotherapy). In most cases, the drug used “is methotrexate, but sometimes cytarabine … may be used as well.” Methotrexate and cytarabine are antimetabolites, which are chemicals that help the body regulate metabolism. The drug mimics intracellular environment, and when “cells incorporate these substances into the cellular metabolism, they are unable to divide.” (13) Antimetabolites target specific phases in the cell cycle. Methotrexate is G1-specific, which prevents the synthesis of mRNA and accordingly, proteins needed for mitosis. When the cell detects an alteration in the G1 phase, it does not transition and go beyond the restriction point into S phase. Cytarabine specifically attacks when the cell is in S phase, which involves replication. One major characteristic of cytarabine is its capacity to inhibit DNA polymerase. The cells ability to phosphorylate is altered and thus the E2F transcription factor remains bound to the RB protein. When E2F cannot be released, transcription is halted and the cell cycle does not progress. (See Figure 5). When the cell cycle is suppressed, cancerous cells, such as the lymphocytes in ALL, will not proliferate.

The next step, consolidation, is typically taken when the leukemia is in remission. Remission is a sign that cancer has lost the battle, but not the war. Drastic measures must be taken in order to combat the persistence of cancer. At this point, doctors turn to intensive treatment options. For ALL, radiation therapy in conjunction with stem cell transplant may be the best option. Radiation acts as a primer in this step of the treatment, in that it is used to kill leukemic cells before the stem cell transplant takes place. In ALL, the bone marrow is affected in such a way that lowers its ability to produce white blood cells. Stem cell transplant is similar to a blood transfusion in which patients “receive the stem cells intravenously”. Once the stem cells enter the bloodstream, they can travel to the bone marrow and begin to produce new and healthy blood cells.

Even with all of cancer’s troops wiped out, it still refuses to wave the white flag. Because of cancer’s deceptive character, we cannot be sure that everything has been done to minimize or even eliminate the disease. While ALL is in remission, the next and final phase is maintenance. For acute lymphoblastic leukemia, “maintenance therapy includes 6-mercaptopurine, methotrexate, steroids, and vincristine” and “intrathecal methotrexate is administered throughout” 6-mercaptopurine is a less intense metabolite used to regulate the rate of cell division, while vinicristine is a plant alkaloid that induces apoptosis. It inhibits the formation of microtubules, and when microtubules cannot form, the cell loses its ability to divide and replicate. Methotrexate is used as a maintenance drug because it prevents cells from developing into the malignant type and maintains “cytotoxic concentrations in sanctuary sites for lymphoblasts”. In these conditions, leukemic cells cannot survive and therefore prevents cancer from further development.

Cancer is relentless. It has no regard for human life. We can do everything it takes to treat cancer, but there is no promise it will not come back. With all treatments in mind, how long can we extend a patient’s life? Is it even significant enough for all the time, effort, and money spent? For Evan, he would typically expect a 40% 5-year survival rate, but with consistent and carefully planned treatment, Evan’s chances of survival are favorable at a 5-year survival rate of 70%. Evan must now evaluate his options. With treatment allowing for a great prognosis, it may seem easy to decide. The best treatment plan has been laid out and it is now up to him whether or not he follows through in hopes of extending his life.

//**Aperçu**//

 Imagine you are a patient with acute lymphoblastic leukemia. Without treatment, you have a 40% 5-year survival rate. But if you could double your chances, would you do it? With treatment such as stem cell transplant in conjunction with radiation therapy, you run the risk of several repercussions such as secondary diseases and cancer, and relapse. If relapse occurs, you’re now only down to a 10% 5-year survival rate. So I leave this proposition on the table. Are you willing to compromise your chances in exchange for hope of life?

__**Works Cited:**__

(1) "Acute Lymphoblastic Leukemia (ALL): MedlinePlus Medical Encyclopedia." U.S National Library of Medicine. Ed. Rita Nanda. MedlinePlus, Mar. 2015. Web. Apr. 2016. <@https://www.nlm.nih.gov/medlineplus/ency/article/000541.htm>.

(2) American Cancer Society: "What is acute lymphocytic leukemia?" "How is acute lymphocytic leukemia classified?" "What are the risk factors for acute lymphocytic leukemia?" "How is acute lymphocytic leukemia diagnosed?" "Treating Leukemia -- Acute Lymphocytic (ALL) in Adults;" and "Response rates to treatment." <@http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/>

(3) The Leukemia & Lymphoma Society: "Acute Lymphoblastic Leukemia". Apr. 2015. Apr. 2016. <@https://www.lls.org/leukemia/acute-lymphoblastic-leukemia?src1=20032&src2=>

(4) Pietrangelo, Ann. "Survival Rate and Prognosis for Acute Lymphoblastic Leukemia." Healthline. N.p., 12 Feb. 2014. Web. 19 Apr. 2016. .

(5) "Acute Lymphoblastic Leukaemia (ALL)." Cancer Research UK. N.p., 7 July 2015. Web. Apr. 2016. <@http://www.cancerresearchuk.org/about-cancer/type/all/>.

(6) Ghazavi, Farzaneh, et al. "Molecular basis and clinical significance of genetic aberrations in B-cell precursor acute lymphoblastic leukemia." Experimental hematology 43.8 (2015): 640-653.

(7) Mullighan, Charles G. "The molecular genetic makeup of acute lymphoblastic leukemia." ASH Education Program Book 2012.1 (2012): 389-396. <[]>

(8) MLA Dang, Vinh T., et al. "Identification of human haploinsufficient genes and their genomic proximity to segmental duplications." European Journal of Human Genetics 16.11 (2008): 1350-1357. <@http://www.nature.com/ejhg/journal/v16/n11/full/ejhg2008111a.html>

(9) Mikkola, Hanna KA, and Stuart H. Orkin. "The journey of developing hematopoietic stem cells." Development 133.19 (2006): 3733-3744. <@http://dev.biologists.org/content/133/19/3733>

(10) Comprehensive Cancer Information. National Cancer Institute. <@http://www.cancer.gov/publications/dictionaries/cancer-terms>

(11) Carroll, W. L. "Safety in Numbers: Hyperdiploidy and Prognosis." Blood 121.13 (2013): 2374-376. Web. <@http://www.bloodjournal.org/content/121/13/2374?sso-checked=true>.

(12) American Cancer Society (2014). Treatting Leukemia – Acute Lymphocytic (ALL) in Adults. Retrieved from <@http://www.cancer.org/cancer/cancercauses/geneticsandcancer/index>

(13) "Cytarabine." Chemocare. Chemocare, n.d. Web. <@http://chemocare.com/chemotherapy/drug-info/cytarabine.aspx>.

(14) "Stem Cell Transplantation for Leukemia." Leukemia Stem Cell Transplantation. N.p., n.d. Web. <@http://www.cancercenter.com/leukemia/stem-cell-transplantation/>.

(15) Seiter, Karen. "Acute Lymphoblastic Leukemia Treatment Protocols ." MedScape. N.p., n.d. Web. <@http://emedicine.medscape.com/article/2004705-overview>.

(16) Mantadakis, Elpis, Peter D. Cole, and Barton A. Kamen. "High‐Dose Methotrexate in Acute Lymphoblastic Leukemia: Where Is the Evidence for Its Continued Use?." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 25.5 (2005): 748-755.

(17) Hayakawa, F. "Acute lymphoblastic leukemia in adolescents and young adults." [Rinsho ketsueki] The Japanese journal of clinical hematology 56.10 (2015): 2032-2038.

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