Essay on Leukemia

Leukemia is a common cancer of the bone marrow. In the United States it occurs mostly in the young and elderly and is associated with down syndrome. This research will go over the back-ground information on leukemia, types of leukemia, demographic, genetic links, and treatment for each types of leukemia.

 There are 3 types of blood cells: erythrocytes, leukocytes, and thrombocytes. The body forms these cells in the process known as hematopoiesis.  Hematopoiesis occurs in the bone marrow, although in fetus it occurs in the liver and spleen (Huether, 497). Leukemia is a cancer which alters the bone marrow to produce abnormal leukocytes known as the leukemic cells (Huether, 564). Leukemia is characterized by the rapid increase of leukemic cells which occupies the bone marrow and lead to less production of normal functioning blood cells (Huether, 526). Leukemia can become malignant fast because leukemic cells can spread quickly to another part of body through the blood vessels.

 To understand the different types of leukemia, we need to understand the differentiation of leukocytes. When bone marrow undergoes hematopoiesis, it produces hematopoietic stem cells which can differentiate into erythrocytes, leukocytes, or thrombocytes, depending on the path it takes. To become leukocytes, hematopoietic stem cells can either differentiate into myeloid stem cells or lymphoid progenitor cells. If it differentiates into myeloid stem cells, it can further differentiate into granulocytes and phagocytes. If it differentiates into lymphoid progenitor cells it will than become lymphocytes, which possesses more specific immune functions (Huether, 494).  Often, leukemia occurs due to abnormal or translocation of chromosomes. To classify leukemia, we look at the cells of origin which is myeloid stem cells or lymphoid progenitor cells. We also look at the rate of progression which can be acute or chronic. Usually when dealing with leukemia that has a sudden onset which involves undifferentiated cells, it is considered acute. Chronic leukemia usually deals with more differentiated cells and will progress more slowly. There are four types of leukemia in total: acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML) (Huether, 526).

  ALL is the most common leukemia seen in children. According to American Cancer Society, it is more prevalent in woman and the risks increase for children under five and older adults over 50. Death from leukemia increase greatly in elderly because they’re not able to withstand the damage done by aggressive treatment, whereas children are able to cope with it much better. ALL is uncommon type of leukemia and it is more common in Whites and Hispanic and less in Blacks (American Cancer Society, 2018). AML is an acute form of leukemia that is more likely be seen in an adult. Unlike ALL, male has more prevalence in being diagnosed with AML but it is more commonly seen in Whites than Blacks as with ALL. Interestingly, risks for developing this type of leukemia greatly increase as household income increases (Goyal. G, 2015). In general, acute leukemia has high prevalence in Whites population and less common in Eastern Europe, Asia, and Central America. However, this doesn’t include Japan due to atomic bombing that occurred during WWII (Huether, 528). Chronic leukemia occurs mainly in adult especially after the age of 40 and rarely in children (Huether, 530). CLL will more likely to develop in men than in women (American Cancer Society, 2018) and increase prevalence in an individual older than 70 (Huether, 530). CML is also seen more in men than in women and also increase prevalence as we age (American Cancer Society, 2018).

 In ALL, there is an abnormal increase in the production of altered lymphoid progenitor cells due to alteration caused in bone marrows. Signs and symptoms become apparent suddenly. Patient may experience fatigue due to anemia. Anemia is present because leukemic cells accumulates in the bone marrow and lead to decrease production of healthy erythrocytes. Hemorrhage also occur due to thrombocytopenia where there is decrease in production of thrombocytes. Fever is also common due to increase in susceptibility to infection. This is because normal functioning leukocytes are reduced which prevent them from fighting pathogens that are harmful to our bodies. Other symptoms may be experienced such as headache, blurred vision, hepatosplenomegaly, and vomiting (Huether, 529). The cause of abnormalities seen in ALL is due to genetic abnormalities such as aneuploidy (Woo, 2014). Aneuploidy is when cells does not contain the normal number of chromosomes which is 46 or 23 pairs. There are different types of aneuploidy such as trisomy and monosomy. In trisomy, there are three pairs of chromosomes so in total there are 69 chromosomes within a cell. Monosomy on the other hand, only contain 23 chromosomes which are not paired (Huether, 42-43). According to NCBI, hyperdiploidy is the most common structural chromosomal arrangement that leads to ALL. Hyperdiploidy occur when there are more than one chromosomes that contain more than one pair. It occurs mainly on chromosomes 4, 6, 10, 14, 17, 18, 21, and X. High hyperdiploidy is associated with alleles PRDM9 which will control the recombination of chromosomes. Hypodiploidy can also lead to ALL although it only affects about 5% of ALL patient (WOO, 2014) Genetic abnormalities also can be due to different arrangements of chromosomes such as translocation where there is change of genetic materials between two different chromosomes (Huether, 48). For example, one translocation that can occur is between chromosome 12 and 21 which occurs in 25% of ALL patients. The section p13 of chromosome 12 which encodes for ETV6 and section q22 of chromosome 21 that encodes for RUNX1 exchange their materials and lead to production of altered lymphoid progenitor cells. Transcription factors ETV6 and RUNX1 are both needed to maintain normal hematopoiesis, however, fusing those two together will disrupt the normal function of these proteins. Deletion or rearrangement can also occur in chromosomes such as chromosome 9p13 which is transcription factors for PAX5 which is also needed for normal hematopoiesis. 32% of patients with ALL are associated with PAX5 mutation (Woo, 2014). Epigenetic factors may also be associated with development of ALL. Epigenetics are turning on and off the genes without actually causing any alteration to the DNA (Huether, 2017). For example, microRNAs regulate the differentiation of hematopoietic cells and its proliferation which may be promoting the development of leukemia. Thankfully there are 90% survival rate for children who suffer from ALL. However, it is very likely to relapse and the survival rate will decrease to 30% the second time. This is most likely due to increase in damaged and mutated cells due to progression and treatment of disease (Woo, 2014).

In AML, there are significant increase in production of myeloid stem cells, which also accumulate in bone marrow and greatly reduce the number of production of other healthy blood cells. Alteration in transcription factor CEBPA is the usual cause of AML and is genetically passed down in autosomal dominant form. CEBPA transcribe into CCAAT enhancer-binding protein alpha which is needed for differentiation within bone marrow and thought to be tumor suppressor genes as well. Therefor alteration in CEBPA is associated with uncontrollable proliferation of leukemic cells. Signs and symptoms are similar to those of ALL. Infection may occur more easily since alteration of CEBPA leads to leukopenia and lose the army to fight off infection. Survival rate for AML is less promising. If it is due to alteration of CEBPA, the survival rate is about 60%. If it’s due to other causes it drops dramatically to about 37.5% (NIH, 2015).     

The most common form of adult leukemia is CLL. The most common cause of CLL is due to deletion of 13q14 chromosome which is also associated with tumor suppressor genes. Surprisingly there are no or only some other chromosomal changes for CLL which indicates that the deletion of chromosome 13q14 is significant in developing CLL. A research found that large chunks of 13q14 was deleted and with further investigation was able to determine that this deletion occur specifically within LEU2 genes of region 29-kb between 2-5 exons. Furthermore, we found that miRNA15 and 16, which are needed for normal lymphocyte production, reside within this deleted region and concluded that this must be connected to development of CLL. As it was hypothesized, studies have found that at least 68% of patients suffering from CLL do in fact has reduction of miRNA15 and 16. It is also found in many other diseases and therefore, we can say that deletion of miRNA15 and 16 have pathogenetic consequences (Croce, 2002).

CML is another chronic, slow developing leukemia usually seen in an older adult. As seen in all other types of leukemia, similar signs and symptoms can be seen. However, in chronic leukemia, as with CLL, when patient is diagnosed with leukemia, they may not have any apparent symptoms. There are three phases to CML. First is the chronic phase. In this phase, there are increase in proliferation of matured leukemic cells and there is significant decrease in the number of myeloid stem cells. This phase last for long periods of time and many patients won’t express any symptoms. The second phase is accelerated phase where myeloid stem cells number slightly increase and symptoms starts to be apparent. This phase is shorter, lasting up to 6 months or may not occur in some patients. The last phase is known as blast crisis where patients experience severe signs and symptoms and is life threatening. The cause of CML is not due to genetic factor and is due to translocation chromosome 9 where it encodes for ABL1 gene and chromosome 22 where it encodes for BCR gene. Individually, BCR gene is known to code for protein that is responsible for cell signaling. ABL1 gene is important for proliferation, differentiation, migration, and apoptosis. When these two genes fuse together, it forms an abnormal gene BCR-ABL1 which is known as Philadelphia chromosome and will promote proliferation and diminish apoptotic function. The proliferation of leukemic cells are so severe in CML that normal blood cells almost diminishes (NIH, 2016).

Treatment for leukemia is mainly done by prolong, aggressive or non-aggressive chemotherapy (American Cancer Society, 2018). Chemotherapeutic agents are used in chemotherapy where each agent will attack specific weak spot and shrink the cancer cells. Therefore, using multiple agents for treatment shows best result, however, because it is also harmful to healthy cells and there are many side effects, not all patients can undergo such harsh treatment (Huether, 260). Chemotherapy is done in three stages. Complete remission is the main goal for the first stage known as induction. During this process patients may stay or spend most of their time in the hospital to prevent developing infection. This process can be quite intense and requires patient to have the therapy done frequently. The second stage is known as consolidation/intensification which is the next treatment that patients go through after they are in remission. Due to high risk of leukemia relapse, this stage continues using high dosed chemotherapeutic agent. Stem cell transplant may also be used to prevent relapse of leukemia. The last, longest stage is known as maintenance which takes in average of two years. According to American Cancer Society, remission of leukemia in adult is very promising although there are high prevalence or relapse seen. If there are no improvement seen by chemotherapy, antibody administration to fight infection may be used to subset signs and symptoms. If there is no available way to treat leukemia, palliative care is available for patients which is to control the symptoms and manage pain (American Cancer Society, 2018).

There are few new preventions and treatments that healthcare providers are trying to invent to improve the management and survival rate of leukemia. For example, there are researchers who found a way to identify risks up to five years before the development of AML. This is surprising because acute leukemia develops suddenly but give the healthcare provider hope to detect this disease early enough to decrease the probability of developing this disease. Researchers have used AML patent’s stored DNA and compared it to individuals who are not diagnosed with AML. We have found that there is translocation of chromosome which encode for ARCH gene and alteration in this gene increase with age. Fusing of genes create abnormal gene known as ARCH-PD which was found in 73.4% of individuals who are at high risk of developing AML (Schieszer, 2018).

Another example is the third generation of Anti-CD20 monoclonal antibodies which are specifically developed to treat CLL which is undergoing clinical trials. Targeting antiapoptotic proteins, this antibody allows normal functioning apoptosis in bone marrow and prevent proliferation of leukemic cells (Robak, 2014).

 As we can see from this research, leukemia is a serious complication that is commonly seen in United States. Patients can achieve complete remission in many cases of leukemia, however, it is also common to relapse with reduced survival rate. Treatments can be very harmful to our body and although many patients benefit from it, palliative care may be the only option left for some patients. There are many treatments that is being developed for clinical trials and we are hopeful to see improvement in increasing survival rate for leukemia.

References

• Huether, Sue and McCance, Kathryn. Understanding Pathophysiology. Elsevier, 2017.
• American Cancer Society. Key Statistics for Acute Lymphocytic Leukemia (ALL). Visited on 7 November 2018. https://www.cancer.org/cancer/acute-lymphocytic-leukemia/about/key-statistics.html. 17 October 2018.
• Goyal. G, et. all. American Society of Hematology. Impact of Socioeconomic, Demographic and Health System Factors on Therapy in Acute Myeloid Leukemia. Visited on 7 November 2018. http://www.bloodjournal.org/content/126/23/3316?sso-checked=true. 2015.
• Woo, Jennifer, et. all. NCBI. Childhood B-Acute Lymphoblastic Leukemia: A Genetic Update. Visited on 7 November 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063430/. 13 June 2014.
• U.S. National Library of Medicine (NIH). Genetic Home Reference. Familial Acute Myeloid Leukemia with Mutated CEBPA. Visited on 7 November 2018. https://ghr.nlm.nih.gov/condition/familial-acute-myeloid-leukemia-with-mutated-cebpa. July 2015.
• Croce, Carlo M. PNAS. Frequent Deletions and Down-Regulation of MicroRNA Genes miR15 and miR16 at 13q14 in Chronic Lymphocytic Leukemia. Visited on 7 November 2018.  http://www.pnas.org/content/99/24/15524. 7 October 2002.
• U.S. National Library of Medicine (NIH). Genetic Home Reference. Chronic Myeloid Leukemia. Visited on 7 November 2018. https://ghr.nlm.nih.gov/condition/chronic-myeloid-leukemia. September 2016. 
• American Cancer Society. Typical Treatment of Acute Lymphocytic Leukemia (ALL). Visited on 7 November 2018. https://www.cancer.org/cancer/acute-lymphocytic-leukemia/treating/typical-treatment.html. 17 October 2018.
• Schieszer, John. Cancer Network. Is Prevention of AML on the Horizon. Visited on 7 November 2018. https://www.cancernetwork.com/acute-myeloid-leukemia/prevention-aml-horizon. 25 July 2018.
• Robak, Tadeusz. Science Direct. New Horizons in the Treatment of Chronic Lymphocytic Leukemia. Visited on 7 November 2018. https://www.sciencedirect.com/science/article/pii/S0001581414000425. June 2014.