Mark Vasserman
Senior Thesis | 2025
Using Bioinformatics to Look for Treatments for Acute Myeloid Leukemia
Abstract
Bioinformatics is becoming increasingly important and prevalent in the world of drug discovery and repurposing. Using the L1000 database, a database containing gene expressions and molecules, the time and resources to discover has been significantly decreased. In this work, potential drug candidates for the treatment of acute myeloid leukemia were looked at using the connectivity map developed by the Broad Institute. Ergothioneine, a well-researched supplement and drug was found to be a possible candidate for treatment for Acute Myeloid Leukemia (AML). After performing analysis with the Touchstone Application, it was shown that the compound is connected to pathways relating to the treatment of AML. Different biological pathways relating to the treatment of AML were identified. The results of this study show promising future research on the treatment of AML. This study shows another potential treatment for AML and how it can be improved.
Introduction
Acute Myeloid Leukemia is a disease that comes from an increased number of myeloid cells in the bone marrow which results in hematopoietic insufficiencies such as a decrease in red blood cell production. Acute Myeloid Leukemia is defined as having more than 30% leukemic blasts in the bone marrow (Lowenberg et al.). Leukemic blasts, also known as granulocytic sarcoma, emerge when there are more than 100,000 white blood cells per cubic millimeter. Symptoms of AML include fatigue, frequent infections, easy bruising or bleeding, shortness of breath,
and unexplained weight loss. AML has a survival rate of 30-40%, although it depends on the age and other factors of the patients. Younger patients have a higher survival rate, and the rate decreases as they get older. Specifically, the incidence of people who have AML is 0.4 per 100,000 for children and increases all the way up to 16.2 per 100,000 for those aged 65 and older (de Rooij et. al). Although not all patients pass away from AML, most of them go through bone marrow transplant and chemotherapy which can permanently alter one's physical health.
One commonality in AML is a mutation in the FLT3 pathway. Fms-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinase family. Tyrosine kinase in an enzyme responsible for adding a phosphate group to the amino acid tyrosine on specific protein substrates which leads to a regulation of many processes, including apoptosis, FLT3 is an important pathway to study because one third of patients diagnosed with AML have a mutation of the gene. The most common mutation of FLT3 is a duplication of the part of the gene, which leads to extra insertions of amino acids into the juxtamembrane domain, the binding site. This internal tandem duplication (ITD) leads to exposing the acceptor sites of the tyrosine kinase domains (TKD) (Meshinchi and Appelbaum). The activation of FLT3-ITD promotes cell proliferation and inhibits apoptosis, which can strengthen leukemia cells and lead to resistance of treatment (Takahashi). Although less common, FLT3-TKD mutations occur in the TKD but also promote cell proliferation and inhibit apoptosis (Liang et al.). FLT3-TKD mutations occurred in 7% of diagnosed adults, and there has not been any FLT-TKD mutations found in children with AML.
Two common drug treatments for AML are daunorubicin and cytarabine. Cytarabine works by being taken up into cells via nucleotide transporters and is then converted into its active form. Cytarabine then is phosphorylated into its active triphosphate form, cytarabine triphosphate (ara-CTP). Ara-CTP and incorporated into
the DNA during the S-phase of the cell cycle. Once incorporated into the DNA, ara-CTP disrupts DNA synthesis and repair. AraCTP inhibits DNA polymerase, further inhibiting DNA synthesis. These can kill the cancerous cells in AML, but can also affect healthy cells, which cause harmful side effects. Daunorubicin is an anthracycline antibiotic and works by inserting into the DNA, disrupting the normal structure, which interferes with DNA replication (Laurent and Jaffrézou). The pathways associated with daunorubicin are influenced by a number of lipid products, reactive oxygen species, oncogenes (such as p53 which is a tumor suppressant), protein kinases such as PCK-3, and phosphoinositide-3 kinase, and other external stimuli (Laurent and Jaffrézou).
Daunorubicin and Cytarabine are examples of chemotherapeutic drugs. To prepare for chemotherapy, tests must be done to ensure that the body is ready to receive the drugs and withstand their impacts. Most chemotherapy drugs are given as an infusion by a tube into the vein in the arm or chest of the patient. Other less common methods of administering chemotherapy as pills and shots. Some common side effects of drug chemotherapy include vomiting, diarrhea, nausea, fatigue, constipation, hair loss, loss of appetite, fever, mouth sores, easy bruising, bleeding, and pain (Mayo Clinic). Most of these side effects can be easily subdued and end upon the completion of the treatment. Some longlasting and permanent side effects include damage to lung tissue, heart problems, infertility, kidney problems, nerve damage, and risk of second cancer. These effects are the main reason why chemotherapy will permanently alter someone's life and why some patients die during the treatment.
The other main treatment for AML is a bone marrow transplant. A bone marrow transplant is the procedure of infusing healthy blood-creating stem cells to replace faulty bone marrow that is not producing enough healthy cells. There are two types of bone marrow transplants, autologous and allogeneic transplants.
Autologous transplants are defined as when the new bone marrow comes from the patient itself while allogeneic transplants are defined when the new bone marrow comes from a donor. Some risks of receiving a bone marrow transplant include stem cell failure, organ damage, infections, cataracts, infertility, rise of new cancer and in the worst case scenario, death (Mayo Clinic, “Bone Marrow Transplant - Mayo Clinic”). A specific risk of allogeneic transplants is graft-versus-host disease (GVHD) in which the new donor cells view the body’s tissues and organs as a foreign threat and attack them. GVHD is quite common amongst patients who receive an allogeneic transplant and although anyone who receives an allogeneic transplant is at risk of getting GVHD, the risk is much higher if the donor and the patient are not related. There are two types of GVHD: acute and chronic. Acute GVHD usually takes place during the first few months after the transplant and its symptoms usually affect the skin, digestive tract, and liver. Chronic GVHD develops later and its symptoms affect many more organs. These symptoms include joint and muscle pain, shortness of breath, persistent cough, vision and skin changes, scarring under the skin and stiffness, rashes, yellowing of the skin and sclera, dry eyes and mouth, mouth sores, diarrhea, nausea, and vomiting. Prior to the transplant, tests are done to assess the health and to see if the patient is well enough to go through with the transplant. For an autologous transplant, the patient will undergo a process called apheresis in order to draw out their own healthy cells. Firstly, the patient receives daily injections of growth hormone to increase cell production inside the blood. Blood is then drawn through a tube and enters a machine which separates the blood from the stem cells. The stem cells are collected and the blood is then returned to the body of the patient. The process for an allogenic transplant is similar for the donor, but on some occasions, the blood of umbilical cords is used in which mothers donate after birth and then are frozen. Afterwards begins the process for conditioning, in which patients are administered a combination of chemotherapy
and radiation that helps kill the cancerous cells. During the procedure, the cells are inserted into the patient through an intravenous catheter in a painless and conscious procedure. The stem cells travel through the blood and multiply, creating healthy blood cells. This process is called engraftment and it at least takes a few weeks for the blood cell count to reach a normal level. After the transplant, the patient is monitored to ensure that they are healthy and medicine may be prescribed to manage effects such as nausea and diarrhea. Although bone transplants show a positive treatment to diseases such as AML, the side effects, including the risk of death, show that there is a need for a drug treatment that has fewer, extreme side effects than chemotherapy.
Another important factor to AML is Mixed Lineage Leukemia (MLL), also known as KMT2A, which comes from chromosomal translocations on chromosome region 11q23 on chromosomes 11. These new fusion proteins act as transcription factors that disrupt normal gene expression. MLL fusions alter chromatin structure and gene expression and lead to homeopathic cell growth, often with other proteins. MLL fusions result in the recruitment of epigenetic modifiers, which lead to changes in histone modifications and chromatin structure. These changes can lead to the activation of oncogenes and inhibition of tumor suppressor genes. Since transcription regulation is changed due to the MLL fusions, hematopoietic differentiation is impaired, leading to the accumulation of myeloid cells, further contributing to AML (Liu et al.).
An important factor that deals with cell death and AML is the B-Cell Lymphoma 2 (BCL2) family. The BCL2 family is a group of proteins that consists of both pro and anti-apoptotic members (Chao and Korsmeyer). The BCL2 gene is anti-apoptotic and prevents cell death instead of promoting cell growth. Overexpression of BCL2 leads to survival of cells, especially malignant ones such as leukemia cells (Irvine et al.). Another member of the BCL2 gene family is BAX. BAX (BCL2 associated
X protein) is a pro apoptotic gene and works directly against BCL2 to keep apoptosis in systems regular. BCL2 is a desirable target for drugs to counteract cancer since inhibiting it could lead to increased cell apoptosis, which could lead to death in cancer cells.
L-Ergothione (EGT) is a naturally occuring amino acid which acts as an antioxidant, protecting cells from oxidative stress (Cheah and Halliwell). Although found in many different foods, it is most predominantly found in mushrooms such as oyster and shitake. Although there have been many in vitro studies proving the effectiveness of EGT, there have not been as many proving the effectiveness in vivo (Cheah and Halliwell). EGT is synthesized when histamine is converted into the precursor molecule 2mercapto histidine. Then 2-mercapto histidine is converted to EGT by a specific enzyme that is currently unknown. EGT is transported into the cells via the carrier Organic Cation Transporter Novel 1 (OCTN1) where it is then distributed to various tissues such as the liver and kidneys. Once inside the cells, EGT undergoes sulfation, when sulfate groups are attached and broken down into various metabolites. Although EGT has plenty of proven health benefits, it is not considered an essential dietary component and there is any proven symptoms due to its deficiency.
The goal of this project was to use bioinformatics to see if L-Ergothioneine has properties that could be used to fight cancer and to use bioinformatics to see if there are any other drugs that have similar properties to L-Ergothioneine.
Methods
CMap and Touchstone applications developed by the Broad Institute were utilized in this study. CMap uses the L1000 Characteristic Direction Signature Search engine (L1000CDS2) which contains a database of millions of gene signatures and molecules. Using Touchstone, perturbational classes of EGT were analyzed, a class in which certain perturbagens share the same mechanism of action. To start off the methods, These genes were inserted into the Broad Institute's Connectivity Map (Cmap) with the upregulated genes inserted into the box labeled upregulated genes and the down regulated genes inserted into the box labeled downregulated genes. The results were analyzed as heatmaps with lists of thousands of compounds, molecules, and genes. The molecules, compounds, and genes at the top of the list had signatures with the most similarities to the input signature, while the molecules at the bottom of the list were opposing signatures. The molecules, compounds, and genes of interest were then placed into Touchstone, where its connections and similar properties to various different perturbational classes were seen by looking at a molecule's connectivity score to that certain class. Touchstone then revealed the perturbagen classes that had the highest connectivity to the molecules. The top 5 most significant perturbagen classes were analyzed in which each class had a connectivity score greater than 90. 90 is the connectivity score used because it is the threshold that CMap uses as it gives a color of connectivity.
Results
The graphs shown are called heat maps and they are the result of CMap. The color under the type shows what the compound is as dark blue are the perturbagen classes and the colors light blue, orange, and purple are compounds.
Figure 1) Top 5 perturbational classes associated with EGT. The red boxes on the right represent the connectivity score between the class with the compound. The darker the red, the closer the connectivity score is to 100 while the lighter the red the closer the connectivity score is to 90. The classes are listed in decreasing order from top down in connectivity score.
Figure 2) Top 60 genes, compounds, and perturbational class members associated with EGT. These are ranked top down with the summary being the red boxes farthest to the right. The darker the red the higher the connectivity score, the darker the blue the more negative the connectivity score is. To the right is the name of the compound, gene or perturbational class member and to the right of that, is a quick description of it.
It was revealed tha EGT has a strong connection to PKC activators with a score of 99.7 (Figure 1). Protein Kinase C (PKC) consists of a family of enzymes in the central nervous system. A protein in the PKC family is p34cdc2 which is regulated by kinases and phosphatases (Lucas and Vıctor Sánchez-Margalet). Activation of this protein can lead to mitotic catastrophe which is similar to apoptosis (Vakifahmetoglu et al.). Mitotic catastrophe results when premature cells enter mitosis and can be caused by chemical or physical stress. The failure of the cell cycle appropriately leads to cell death. Although untested, EGT could cause these stresses which is a potential target to study. This is useful in the study of AML as apoptosis of leukemic cells is the cure and PKC activators could be a target. PKC Activators have been shown to cause death in Bronchial Epithelial Cells (Kim et al.). After phorbol ester, which is a tumor promoter, Phorbol 12, 13-dibutyrate (PDBu) was stimulated on bronchial cells, microarray analysis showed that PKC activators decreased cell viability within 6 hours (Kim et al.). Since PKC activation decreased cell viability and increased apoptosis in bronchial cells, it can possibly relate to AML cells.
Secondly, EGT has a strong connection to Nuclear Transcription Factor KB (NFKB) activation with a score of 100.00. NFKB is actually not a single gene but a family of similar transcription factors that consist of NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), c-Rel and RelB (Dolcet et al.). These genes are involved in illnesses, inflammatory diseases, apoptosis, and cancer. Specifically in daunorubicin, upon activation, it disassociates from Ikb (alpha), an inhibitory subunit of NFKB, translocates to the nucleus, and then binds to the nucleus where it can regulate the expression of many genes (Sun and Andersson). Since NFKB activation has been shown in x, a prescribed and
studied drug for AML, it is a very probable target to study more and with EGT having the highest connection score, it shows a lot of promise. Since apoptosis is such an important part of curing AML, targeting NFKB could very well be an important factor to curing AML. NFKB has been strongly linked to cell proliferation and inhibition of apoptosis (Lawrence). Like PKC activators, NFKB activation has been shown to increase inflammation to fight diseases. Although NFKB is anti-apoptotic in inflammatory cells, It is also shown to be pro-apoptotic in anti inflammatory situations so NFKB activation could be an important factor in any new drugs helping cure AML. Specifically, EGT also has a strong connection to protein synthesis inhibitors with a score of 99.59. Protein synthesis inhibitors are a type of compound that prevent DNA from synthesizing proteins (Davis and Squire). Antibiotics are one type of protein synthesis inhibitors such as Tetracyclines and Macrolides which inhibit binding of aminoacyl t-RNA to the ribosome and binding to the RNA respectively. Other cancer treatments are protein synthesis inhibitors such as cycloheximide and Chloramphenicol. Dactinomycin is a specific protein synthesis inhibitor which treats a multitude of cancers such as cancers of muscles and soft tissues. It can be prescribed by doctors and kills cells but also has the side effect of hair loss.
EGT also has a strong connection with ATPase inhibition with a score of 99.08. ATPase (or the sodium potassium pump) is a transmembrane protein complex that regulates and maintains the ionic and osmotic balance in cells (Song et al.). Using MCTS modeling, ATPase inhibitors such as ouabain and digoxin upregulated apoptosis markers in Hepatocellular carcinoma (HCC) or liver cancer. There are different types of ATPase such as V-type ATPase (V-ATPase), P-type ATPase, and F-type ATPase (ATP Synthase) (Pérez-Sayáns et al.). V-ATPases have been shown to trigger apoptosis through caspase-dependent and caspaseindependent mechanisms. Plasma membrane V-ATPases help regulate cytosolic pH in white blood cells and neutrophils. This
mechanism is also used by tumor cells, which produce more hydrogen due to high glycolytic activity. Since V-ATPase has been shown to prevent apoptosis, its inhibition would clearly prevent cell proliferation and promote apoptosis. Since other drugs that are ATPase inhibitors have been shown to have pro apoptotic effects, ATPase inhibitors are shown to be an important factor in developing a drug to cure AML (Alevizopoulos et al.).
Finally, EGT has a connection to IKK inhibitors with a connection score of 94.70. IKK inhibitors regulate transcription factor NF-kB by first blocking the kinase activity of IKK proteins (Castro et al.). This prevents IkB from being phosphorylated and therefore cannot be degraded.The lack of degradation means that NF-kB is nor released and translocated into the nucleus One article showed that IKK inhibitor PS1145 induced Nf-KB in activity in PC cells (Yemelyanov et al.). IKK inhibitor PS1145 also induced apoptosis and inhibited proliferation in PC cells. An MTT test revealed that there was a 30%-35% decrease in DU145 cells. The number of cells in the s-phase decreased by 32% with an error margin of 3.25% after being treated with PS1145 for 72 hours (F. Liu et al.). The inhibition of proliferation was further seen as the decrease of K67 protein expression that is known to be expressed in G1, S, G2, and M phases of the cell cycle. A lack of Nf-kB can lead to curing inflammatory diseases but more importantly, it decreases cell survival.
Novel Drug Proposal
Here is a proposal for a new and improved drug that could be useful in the treatment of AML using CMap and touchstone. Anisomycin is such a drug that is predicted to be better than Ergothione in treating AML. In the CMap query, anisomycin is
listed as the 17th top compound. With such a high ranking, anisomycin could have strong potential to treat AML.
Figure 3) Top 5 perturbational classes associated with anisomycin. The red boxes on the right represent the connectivity score between the class with the compound. The darker the red, the closer the connectivity score is to 100 while the lighter the red the closer the connectivity score is to 90. The classes are listed in decreasing order from top down in connectivity score.
Analyzing anisomycin shows that it has strong connections with peturbational classes analyzed in EGT. For instance anisomycin has a connectivity score to PKC activators with 99.65 just like EGT. Anisomycin had the strongest connections to protein synthesis inhibitors, atpase inhibitors, and ikk inhibitors, all which EGT had connections to but anisomycin had and even higher connectivity score of 99.86, 99.77, and 99.44 respectively.
Anisomycin also had strong connectivity scores of other peturbational classes such as HIF activators and MTOR inhibitors. Hypoxia-inducible factor-1 (HIF1) has been shown to increase apoptosis when overexpressed (Ziello et al.). Although the exact means of how this works is unclear, it's known that when tumor suppressor p53 interacts with the HIF-1 protein, it is stabilized, it activates genes such as p21 which leads to apoptosis (Zhang et al.). Mechanistic target of rapamycin (mTOR) mTOR has been shown in many studies to increase cell apoptosis and because of that there are many MTOR inhibitors in clinical testing to see if they can be potent anti-cancer drugs (Zheng and Jiang).
Discussion
CMap and touchstone are useful tools that can help enhance the drug discovery process. Previously researchers would spend many resources and time to discover the pathways of potential drugs and compounds, but now software can help expedite the process and the time can be used to test these possible compounds. The L1000 dataset is fundamental because it contains millions of gene sets and compounds that can be used to help predict possible treatments. Using this technology EGT was identified as a possible treatment to AML through its possible pathways that lead to cell apoptosis. Not only can this software be used to find potential drug targets, it can also easily reveal the more obscure pathways and connections between proteins. Another drug, anisomycin was also identified as a possible treatment. The understanding of human diseases can be accelerated and with further development of AI, can be even more increased and sped up.
There is current research being done on anisomycin and how it can be a potential treatment to AML but this paper shows how many different pathways are possible solutions to the treatment. Anisomycin has been shown to disrupt mitochondrial
respiration in cells which is then followed by apoptosis. In a study, Anisomycin has been shown to induce apoptosis in osteosarcoma cells, a different type of bone cancer. The inhibition of anismycin works by targeting mitochondrial biogenesis. Many cells targeted by anisomycin stayed into the g2/m phase in the cell cycle, therefore inhibiting cell cycle progression and proliferation. This is promising but looking at the more obscure pathways mentioned could lead to more results and validation of anisomycin as a treatment to AML.
Validations of EGT as an anti-cancer drug.
Although EGT is a prescribed drug that has a multitude of health benefits, it is not highly researched in the anti-cancer sense. One way to validate EGT as an anti-cancer drug is by utilizing mice. Since mice are mammals and have similar biological processes to humans, they are the best living organism to test drugs on. In vivo testing is vital and cell apoptosis in mice should be measured to see if EGT is a viable ant-cancer treatment. Afterwards, if it is shown to be viable, EGT can be tested on actual humans with AML.
One case that can fault EGT is that it did not have a high connection score FLT3 Inhibitor perturbagen class with only a score of 40.98. FLT3 Inhibitors have been heavily linked to AML and have been a strong target for treatment. Since EGT does not have a promising connection score, it casts a shadow of doubt that it can be used as a treatment for AML. Another fault of EGT is that it only had a connection score of 64.63 to BCL inhibitors, ranking it the 13th highest perturbational class. Since inhibition of BCL2 has been already shown to be an important factor to induce apoptosis in cancers, EGT might not be the most ideal drug for testing but it cannot be fully shown until further testing is done On the other hand, Anisomysin has a connectivity score to
perturbagen class of FLT3 Inhibitor of 98.52. While this is a relatively high score, it is only the 16th highest ranked perturbagen class. Although showing great potential. On the more positive side, anisomycin has a connectivity score to BCL inhibitors of 99.87 which is very high and ranks it as the eighth highest perturbagen class associated with it. This shows that a lot of promise as anisomycin has a strong connection to a studied purtabagen class that is known to cause apoptosis. There have also been a few studies that have shown that Anisomycin is capable of targeting AML cells (Cao et al.)
Although CMap is very useful, this study has its limitations as other data sets and tools exist. L1000 Characteristic Direction Signature Search engine (L1000CDS2) is a database that uses only a subset of the L1000 database and using it along with CMap would help support the data derived from CMap. The biggest flaw of this study is that the entire work done here is hypothetical. The proposal of EGT and anisomycin as a potential anti-cancer drug only has meaning if these compounds can go through rigorous invivo testing to ascertain the acti-cancer potential of them. The only way to fully confirm the results is to go through the full medical processes that all the other prescribed drugs go through. Future work on the theoretical side includes analyzing more compounds shown by Cmap as time was a large limitation of this project. The more obscure perturbagen classes with a lower connectivity score should also be analyzed because all the potential connections should be analyzed.
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