Acute Lymphocytic Leukemia and CAR-T therapy

Abstract

This project explores explores the genetic basis and advanced treatments for Acute Lymphocytic Leukemia (ALL). ALL is an aggressive blood cancer primarily affecting children, characterized by the abnormal proliferation of immature lymphocytes. The ETV6-RUNX1 translocation, occurring in 25% of ALL cases, disrupts hematopoiesis and requires a "second hit" for leukemic transformation, highlighting its complex genetic origin. Symptoms of ALL range from fatigue and weight loss to severe immune dysfunction. Diagnosis involves blood tests, bone marrow analysis, and spinal fluid tests. Treatments include chemotherapy, targeted drug therapies, stem cell transplants, and advanced immunotherapies like CAR-T cell therapy. CAR-T therapy involves engineering a patient’s T-cells to target leukemia cells expressing CD19. Although highly effective, CAR-T therapy is expensive and primarily reserved for relapsed or refractory cases. The study emphasizes the need for more targeted therapies, including multi-protein targeting CAR-T therapies and exploring epigenetic therapies to prevent leukemic transformation. Further research into the genetic and epigenetic factors behind ETV6-RUNX1 could refine therapies and improve outcomes for pediatric ALL patients, making treatments safer, more specific, and widely accessible.

ETV6-RUNX1 translocation and its effects on the expression of genes(Figure representation created by the author:Rachel Daniel)

Background

Acute lymphocytic leukemia (ALL) is a fast-growing, aggressive type of blood cancer that occurs when there is an abnormal proliferation of immature lymphocytic white blood cells. It is classified into two main subtypes based on the type of white blood cell affected: B-cell ALL: The most common subtype affecting B-cells that produce antibodies and help fight infections, accounts for almost 85% of ALL cases. T-cell ALL: Affects the T-cells that destroy germs and support other immune system cells.T-cell ALL accounts for 15% of ALL cases. B-cell ALL predominantly affects children below the age of 15 and is most prevalent in ages 1-4 years. The five-year relative survival rate of B-cell ALL is 72%. There are a variety of risk factors that could lead to the development of ALL. Some of them are: Previous treatments for cancer, exposure to radiations or benzene and genetic mutations. People also affected by inherited genetic conditions like down syndrome and bloom syndrome are at a higher risk of developing ALL.

Research Hypothesis

My hypothesis for this research is that children with ETV6-RUNX1 translocation are more susceptible to develop B-cell ALL at an earlier age as ETV6-RUNX1 translocation is found to occur in 25% of patients diagnosed with ALL. This translocation causes these genes to stop functioning appropriately in chromosomes 12 and 21 which leads white blood cells to lose their function.

Results

This graph shows the most commonly mutated genes found in patients with ALL along with their prevalence percentage.

I conducted in depth research of genetic mutations in B-cell ALL. I found many mutations (listed and plotted below) that are mutated at a high rate. In the etiology of childhood ETV6-RUNX1 ALL is not very well understood. Translocation could be a key/initiating event during foetal growth but a second mutation once the child is born. However, to fully understand the genetic evolution of E/R-positive ALL, identification of the entire spectrum of genetic changes that accompany this fusion gene is necessary. The ETV6 gene is located on the short arm of chromosome 12 at position 12p13.2. It encodes a transcription factor that is involved in embryogenesis, blood vessel formation, and the regulation of haematopoiesis.
The RUNX1 gene is located on the long arm of chromosome 21 at position 21q22.12. It also encodes a transcription factor that plays a role in haematopoiesis and in defining haematopetic stem cells.
When an ETV6-RUNX1 translocation occurs, it prevents these genes from doing their job.
One of the most recent treatments that has been approved for Acute Lymphocytic Leukemia is CAR-T cell therapy. Tisagenlecleucel is a type of CAR T-cell therapy that targets the CD19 protein on cancerous leukemia cells, specifically ALL cells. This therapy was approved on August 30th, 2017 for treating patients under the age of 25 diagnosed with ALL.

Conclusion

I have concluded that my hypothesis cannot be proved or disproved without further research. The cellular framework in which ETV6-RUNX1 translocation arises and the maintenance of a pre-leukemic condition by this mutation are fundamental to the mechanism that underlies leukemogenesis. I can conclude that ETV6-RUNX1 translocation might be the primary driver of B-cell ALL. Once the leukemic cell has the primary translocation, it only needs one more mutation to become cancerous.
ALL is a dangerous and aggressive cancer that can be aggravated due to other complications making it difficult to treat. The availability of various treatments helps combat individual cases as well, but the efficiency of treatments is not good. ALL is a rather difficult cancer to work on as it is most prevalent in pediatric patients. But, this means that the treatments also need to be safe for said age group. One way to advance in this field is to research more on the origins of ALL. The medical field is always evolving and there are already efforts to find a new treatment for ALL. I hope that the medical field and research field can work together to treat and prevent ALL, especially in pediatric patients.

Future directions of research

While recent advancements on treatments for ALL have improved, they have not yet been refined or made accessible. Making CAR-T cell therapy more specific to the cancer cells could be a potential first step. Right now, Tisagenlecleucel only targets the CD19 protein on cancer cells, but it would be beneficial to target multiple proteins that exist on the cancer cell for faster and more accurate treatments to occur.
It would also be useful to explore causes for ALL other than ETV6-RUNX1. This way, there would be more treatments catered to a variety of patients.Consequently, other forms of treatment could also be explored for ALL. Recently, epigenetic therapy has resurfaced as an area of research for ALL. As epigenetic factors could be responsible for actually causing leukemic cells to develop, preventing that from occurring could prevent the growth of ALL.
But, to prove this form of treatment, the two-hit model of ETV6-RUNX1 and ALL would have to be proved. There has been no research done on the occurrence of ETV6-RUNX1 translocations on people that do not develop ALL.