A paper based on research done on a newly developed leukemia drug and its mechanisms within the cell, written for Cell Biology in Fall 2018.

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Leukemia Research Paper

                Acute myeloid leukemia, or AML, is an aggressive, typically-fatal cancer characterized by the presence of immature leukemic blasts in the body’s bone marrow and other tissues (Minzel et al., 2018). I have experienced some of the troubles associated with this particular cancer, as my younger cousin was diagnosed with AML last year; her doctors now claim she is in remission. As someone who is highly interested in both research and medicine, and having seen my family struggle with the diagnosis of my cousin, this topic in particular was a very stimulating and informational source of knowledge and understanding for me. The mechanisms that the authors of this study used in order to develop a way to increase cell apoptosis in AML cells without affecting normal cells in other tissues is highly interesting to me, since I am used to hearing about more “traditional” (and harmful) forms of eradicating cancer, such as radiation and chemotherapy.

The purpose of this study was to find a new way to treat leukemia and possibly other cancers by stimulating cell apoptosis (programmed cell death), which is usually suppressed in cancerous cells. In this study, the researchers were attempting to improve AML treatments by activating p53, a protein that suppresses tumor activity by activating the intrinsic cell apoptotic pathway with the additional help of H2AX and Caspase 3 (Fridman and Lowe, 2003). Typically, p53 is suppressed due to multiple antagonistic mechanisms, but can be activated by inhibition of casein kinase 1A1 (CK1α), which is the main focus of this study. CK1α also is involved in the phosphorylation of beta-catenin, a protein that, when overexpressed, results in cancer. The researchers focused on small molecule inhibitors as treatments, in particular six pyrazole-pyrimidine scaffold molecules (A-series) that, after some molecular tweaking, exhibited CK1α inhibitory activity (Minzel et al., 2018). After inoculating groups of mice with AML cells, the researchers administered the small molecule drug treatments to determine if they would inhibit CK1α activity, and therefore stabilize p53 and beta-catenin, induce the DNA damage response (DDR), and activate the intrinsic apoptotic pathway and the caspase cascade in order to induce apoptosis.

The small molecule inhibitors that are used in this study replicate the effects of CK1α ablation, which results in the stabilization of p53, thus inducing the DNA damage response (DDR) by the phosphorylation of H2AX. P53 then activates the intrinsic apoptotic pathway, cytochrome C is released from the mitochondria of the cell, resulting in the activation of the enzyme caspase-3, which then leads to the caspase cascade and ultimately, apoptosis (Wikipedia, 2018). The six small molecule inhibitors that were used are A14, A75, A51, A47, A86, and A64. Out of those six, four of the inhibitors (A86, A51, A75, and A14) were found to be very effective at inducing leukemia cell apoptosis, mainly due to their ability to stabilize p53 (Minzel et al., 2018). The two inhibitors that showed the most promise were A51 and A86. These two inhibitors in particular showed stabilization of p53, reduced phosphorylation of beta-catenin (indicating its stabilization), increased phosphorylation of gamma-H2AX (which then initiates the DDR). This is also due to their strong inhibitory effects on transcriptional kinases CDK7 and CDK9, which are involved in transcriptional initiation and elongation, respectively. The effects of the inhibitors on CDK7 and CDK9 resulted in decreased transcription in the AML cells, decreased proliferation of their cell cycles, and ultimately the death of the AML cells.

The mice that were afflicted with AML were treated with A51 or A86, with improved conditions shortly after their doses. Even just at 5 to 6 hours post treatment, leukemic bone marrow cells from the afflicted mice were showing signs of increased DDR, p53, and caspase 3 activation. By 16 hours post treatment, leukemic cell counts in bone marrow and blood samples were down to 5 to 10%, and additionally, drastic reduction of spleen mass, reduced cellularity and improved color change of the bone marrow due to AML cell apoptosis (Minzel et al., 2018). Tissues obtained from the treated mice displayed that treatment with the inhibitors relieved many of the AML symptoms from the bone marrow, spleen, liver, and blood of the afflicted mice, but did not affect non-leukemia-affected tissues, like the intestines, heart, and lungs. This indicates a selective sensitivity to the AML cells by the CK1α inhibitors. Mice treated with the inhibitors typically survived, especially when also given a bone marrow transplant from mice that had been “cured” of AML with the inhibitors.

This treatment seems to be very effective, as it selectively triggers apoptosis in leukemia cells without harming unrelated cells in other tissues, which is a markedly important hurdle to have overcome in treatment of cancers, since typically most cancer treatments are invasive and destructive to the body as a whole, and involve subjecting the body to cytotoxic treatments in the hopes that the cancer will be destroyed by the treatment before the healthy tissues will. I do believe that the researchers involved in this study successfully achieved their goal, since their results and findings indicate that the inhibitors cure the afflicted mice by selectively killing AML cells without harming healthy cells with the activation of p53. I would recommend these drugs be used therapeutically on humans, even though the possible side effects or consequences of small molecule inhibitors are not fully known. I have seen the destructive effects of chemotherapy and radiation firsthand on family members that were unfortunately diagnosed with cancer, and have even seen immunotherapy treatments that were also supposed to be “preferable” to cytotoxic treatments like chemotherapy. I believe that if more drugs could be manufactured to specifically target cancerous cells on a molecular basis, as the researchers have done in this study, then maybe less people could suffer through traditional cancer treatments only to be defeated in the end by the same medicine. I think that drugs such as these small molecule inhibitors are truly the future of cancer treatment, and could lead to improved lifespan or even just quality of life for those that are afflicted with cancer.

Works Cited

Minzel, W., Venkatachalam, A., Fink, A., Hung, E., Brachya, G., Burstain, I., Shaham, M., Rivlin, A., Omer, I., Zinger, A., Elias, S., Winter, E., Erdman, P., Sullivan, R., Fung, L., Mercurio, F., Li, D., Vacca, J., Kaushansky, N., Shlush, L., Oren, M., Levine, R., Pikarsky, E., Snir-Alkalay, I. and Ben-Neriah, Y. (2018). Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. [online] Cell. Available at: https://doi.org/10.1016/j.cell.2018.07.045 [Accessed 2 Dec. 2018].

Fridman, J. and Lowe, S. (2003). Control of apoptosis by p53. [online] Nature. Available at: https://www.nature.com/articles/1207116 [Accessed 2 Dec. 2018].

Helton, E. and Chen, X. (2006). p53 modulation of the DNA damage response. [online] Prospects. Available at: https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcb.21091 [Accessed 2 Dec. 2018].

Wikipedia. (2018). Apoptosis. [online] Available at: https://en.wikipedia.org/wiki/Apoptosis [Accessed 2 Dec. 2018].