Jasmine Naranjo Professor Steel, Christina BIOL 293 Fall 2018
Acute myeloid leukemia
“The ultimate measure of a man is not where he stands in moments of comfort and convenience, but where he stands at a time of challenge and controversy.” – Dr. Martin Luther King Jr.
Cancer is not a word that anyone wants to hear at a doctor’s visit, fortunately for many patients they stand up to fight to become survivors. Due to my future chosen field in public health this specific article of acute myeloid leukemia, drug development, testing, apoptosis and its cell cycle is particularly interesting. I aspire to be involved in research and case studies of drug development to make sure it’s safe for the public. The purpose of this article is to evaluate the different drugs used in a trail to see if it killed or slowed down leukemia cells from replicating. Acute myeloid leukemia also known as AML is an aggressive hematologic malignancy, caused by the accumulation of immature leukemic blasts in the blood and bone marrow. The study was conducted on AML sick mice treated with the indicated inhibitors to evaluate if there was any change in killing of the leukemia cells or slowing down replication. Understanding the cell cycle plays a big part in evaluating how does leukemia come about, because it causes damage to the DNA of developing cells in your bone marrow. The stage in between Growth, and Replicating DNA, there is a process that it stops to check if the DNA is healthy enough to replicate. If the DNA is damage, there is a protein called p53 that notices and stops the cell cycle. Once the cell cycle stops, it evaluates if it can repair the damage if it can’t repair the damage it will begin a process called apoptosis. When you phosphorylate B-catenin, it triggers it for degradation causes to break down the cell and not accumulate. CK1a doesn’t phosphorylate B-catenin which accumulate cells then translocate in the nucleus to act as a transcription factor. Therefore, activates the accelerated cellular replication which leads to leukemia. Apoptosis is a way for the cell to die, initially created in this research article to lead to an intrinsic pathway. Mitochondria ruptures and floods the cell which is very damaging to lead to apoptosis where the cell actually dies.
Throughout the study, data was taken, and presented in figures 1-4 which lead to several different outcomes of which drug did better. For example, figure 1.C: dissociation constants/ binding affinity is a chart with numbers and a few drugs listed; looking for the Kd. It shows how strongly does it bind to the CK1a protein, which is on the far-left column and across you have the drugs A14, A47, A51, A64, A75, A86. The rule of thumb is the lower values indicate stronger binding; A14, A75, A51, A47, A86, A64; based on binding affinity to CK1a, A14, and A75 would have the strongest effect. Figure 1.E-F: western blots with concentrations is a chart with smears of black bands from light to very thick which are for protein detection. The rule is the thicker the band shows the more protein that has been detected. CK1a on the shCont protein is present and the far-right side, shCK1a is absent which knocked out the gene. Indicators of concentrations of the bands get darker from right to the left and would show if the drug is dose dependent. Panel F shows CK1a for A14 decreases very slightly from the original, A47 is lighter and volume slowly increases. A51 indicators of concentration becomes thicker and darker from the original CK1a, and A64 shows a slow decrease in concentration. A75 starts off very light compared to the original CK1a but slowly increases, and so does A86. Figure 2.A: Staining for Annexin V would show which drugs caused apoptosis. Early steps in apoptosis is that it flips on the outside and that’s how you can visually see on the graph that both A51, A86 that caused the most apoptosis. Figure 2.D Spleen and Bone Marrow are characteristic of AML mice which A51 showed signs of AML improving by appearance compared to control. Figure 2.F-G shows mice tissues with AML; Bone Marrow, Spleen, Liver, Blood Smear, Intestine Lung. The bottom row show mice after eighteen hours from indicated inhibitors; the liver, bone marrow, spleen, and blood seem like the most improved. Figure 3.D, E, G are survival curves and notifies you which mice stayed alive from beginning to end throughout time. It showed some of the treated mice still died but half of the treated mice lived. Figure 4.E showed that A86, and A51 have the strongest effect on Caspase 3, p53, and yH2Ax because it shows the most protein.
Therefore, the author’s goal was to achieve results that he saw improvements in mice over time and the data supported his summary. I personally believe he was spot on concerning the possibility of seeing improvements in mice with AML, but I am unsure if it’s a cure for human leukemia. Before it would go through trial studies, I suggest the case study on the mice should be conducted at a larger scale and throughout time; depending if the results show significant improvements. Hopefully, we are on the right track to supporting a potential efficacy in curing human leukemia especially with our medical advancements. This case study opened the door to a possibly of finding a cure to AML in the future, it’s the first step into the right direction.
Citation
Minzel, W., Venkatachalam, A., Fink, A., Hung, E., Brachya, G., Burstain, I., Shaham, M., Rivlin, A., Omer, I., Zinger, A. and al, e. (2018). Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell, [online] 175(1), pp.171-185.e25.
AML: page 171; see also: Internet
Β-catenin: Wikipedia, especially the section on involvement in cancer
CDK7: page 175
CDK9: page 175
Caspase 3: Wikipedia