By Medha Lolayekar, Lynbrook High School, San Jose, California, USA
With an estimated 14 million new cases and 8 million cancer-related deaths in 2012, the World Health Organization (WHO) projects that by 2035, the world could see 24 million new cancer cases and 14 million cancer-related deaths each year (Antoni et al., 2016). Cancer is undoubtedly a major global health issue.
Acute Myeloid Leukemia (AML) is the most common type of blood cancer, with hundreds of thousands of people either currently battling the disease or in remission (LLS.org, 2020).
While advanced technologies are available at our fingertips, the existing treatments for AML have not significantly progressed in the last 40 years. Intensive chemotherapy is a typical treatment for AML. However, appropriate treatment is complex and often not feasible, especially in low- and middle-income countries (Union for International Cancer Control, 2014). In the United States, where a “one-size-fits-all" approach to treatment is often utilized, the 5-year survival rate for people 20 and older diagnosed with AML is about 25%, while for younger patients, it is less than 70% (Cancer.Net, “Leukemia - Acute Myeloid - AML: Statistics“, 2020).
The Human Genome Project, followed by the establishment of the International Cancer Genome Consortium, enabled scientists to understand the nature of cancers. Recognizing the need for individualized treatment, in 2015, a nationwide initiative called the Precision Medicine Initiative (PMI) was launched. PMI’s short-term goals included expanding precision medicine in the area of cancer research. It was tasked with bringing together multidisciplinary research teams to look for effective interventions and treatment strategies.
In comparison to chemotherapy, targeted therapies were found to have fewer adverse effects and greater efficacy. Targeted therapies have changed the landscape in AML treatment, improving survival and quality of life (Yu et al., 2020). However, AML has many subtypes and different gene mutations, thus making it hard to find a complete cure.
AML is caused by a mutation in the deoxyribonucleic acid (DNA) sequence in hematopoietic stem cells (HSCs) (Cancer.org, 2018). The HSCs renew themselves and divide to create new cells forming into many types of blood cells (National Institutes of Health, 2001).
The mutation causes overproduction of abnormal white blood cells and displacement of healthy blood cells. At this point of illness, the patients begin to experience symptoms of Leukemia such as fatigue, easily bruising, and frequent infections (National Health Service, 2019).
Mutations in certain genes cause the manifestation of AML, while other genes could be used to prevent AML from advancing; by looking into each mutated gene’s direct binding regions, it is possible to block their expression through inhibitor-molecules and slow the rate of AML progression (Lagunas-Rangel et al., 2017).
In the summer of 2020, I participated in a translational cancer research project that focused on the identification of inhibitors affecting the regulatory regions of selected genes involved in AML. There are nearly two dozen significantly mutated genes in AML. The results of DNA sequencing for over hundreds of patients with AML demonstrated that almost 80% of patients had at least one of these gene mutations (DiNardo, & Cortes, 2016). Of these genes, the first gene of interest in my research was CEBPA, which provides instructions for making a protein called CCAAT Enhancer-Binding Protein Alpha (National Institutes of Health, 2020). This protein attaches to specific regions of DNA and helps control genes’ activity. The CEBPA is known to mutate in some AML patients, fueling the progression of AML. The second gene of interest provides instructions for making a protein called runt-related transcription factor-1 (thus the name - RUNX1). Like other transcription factors, the RUNX1 protein attaches to specific regions of DNA and activates genes that help control blood cell development. RUNX1 is principal in the development of hematopoietic stem cells (Mill et al., 2019).
I was able to identify direct binding between RUNX1 and CEBPA. As RUNX1 directly binds to CEBPA and CEBPA is a known gene that causes AML, it is possible to inhibit the expression of CEBPA by finding an inhibitor for RUNX1. CEBPA itself does not have any known inhibitors; the only way to block its expression is through direct binding of another gene.
Future tests and research on the efficiency of the inhibitor could result in a new targeted treatment. While my research could not produce immediate or practical results, it may bring us closer to a breakthrough. It is a humble contribution to research efforts by established scientists working with global health organizations focused on cancer prevention, control strategies, diagnostic tools, and cost-effective access to treatments. The rising projection of AML cases makes the search for targeted therapies ever so urgent.
References
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Mill, CP., Fiskus, W., DiNardo, CD., Qian, Y., Raina, K., Rajapakshe, K., Perera, D., Coarfa, C., Kadia, TM., Khoury, JD., Saenz, DT., Saenz, DN., Illendula, A., Takahashi, K., Kornblau, SM., Green, MR., Futreal AP., Bushweller, JH., Crews, CM., & Bhalla, KN., (2019, April 25). RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1. (n.d.) Retrieved October 03, 2020, from https://pubmed.ncbi.nlm.nih.gov/31023702/
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Yi, M., Li, A., Zhou, L., Chu, Q., Song, Y., & Wu, K. (2020, June 08). The global burden and attributable risk factor analysis of acute myeloid leukemia in 195 countries and territories from 1990 to 2017: Estimates based on the global burden of disease study 2017. [Illustration]. Retrieved November 30, 2020, from https://jhoonline.biomedcentral.com/articles/10.1186/s13045-020-00908-z/figures/2
Yu, J., Jiang, P. Y. Z., Sun, H., Zhang, X., Li, Y., & Song, Y. (2020, May 20). Advances in targeted therapy for acute myeloid leukemia. Retrieved November 28, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238648/
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