Preclinical Models for co-targeting CK1a for AML Leukemia

Cancer such as leukemia is a rapid growth of damaged cellular development that causes blood to form in tissue and in bone marrow. When this happens, this causes the body to poorly fight infection as “the bone marrow produces abnormal white blood cells, which don’t function properly” (Mayo Foundation for Medical Education and Research, 2018). “Small Molecules Co-targeting CK1a and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models” article refers to the acute myeloid leukemia (AML) type of leukemia cancer. Like most cancers, P53 is an activation site that checks for proper DNA before replication. However, when DNA or cells are damaged through the G1 process, or cellular growth cycle, the cells go through apoptosis to rid itself from duplicating other damaged cells and causing this malfunction within the cells that ultimately causes cancers to form: including leukemia.

For individuals who have AML, it is where immature myeloid cells start to form in the bone marrow and in the blood. This rapid formation interferes with the blood stem cells of white and red cells, as white blood cells cannot properly fight off bacteria and diseases as they normally do because of the rapid immature functioning growth. As there is damage to DNA, as a break occurs in the double stranded helix, called a gamma- H2AX. The Gamma- H2AX break becomes detected by p53. For individuals with leukemia, p53 works as a tumor suppressor. P53 “is responsible for detecting DNA damage, chromosome abnormalities and arresting the cell cycle to initiate repair; if repair is not possible then apoptosis is induced” (Samarasinghe, 2013). However, phosphorylation by casein kinase 1A1 (CK1a) in p53 on Thr18 helps to stabilize the protein. In activating it, “p53 is induced by some AML treatments that interact with chromatin regulators,” or DNA histone protein site (Minzel et al., 2018). By CK1a inhibitors also activating p53 in certain individuals this allows for the cancer to rid itself.

In an “effort to the identification of CDK-subtype selective inhibitors has been made to optimize therapeutic success and minimize side effects for cancer patients” (Graf et al., 2011). By destroying leukemic cells, CK1a inhibitors does this by co-targeting Cyclin-dependent kinase (CDK) 7/9. In which CDK7 enables transcription while CDK9 assists in transcription elongation. CDK7 also assists in cell cycle progression and the phosphorylation of RNA polymerase II at Ser5 and Ser7 and CDK9 phosphorylates RNA polymerase at Ser2. Moreover, β-catenin on the other hand is a cell regulating protein that proliferates, or increasing, gene expression of cells which increases leukemic cells to develop if not stopped. However, caspases 3 protein mediates β-catenin’s formation and starts the programing of apoptosis, or the cell death cycle.

In this preclinical model they examine mice and how the protein ‘p53’ may be activated by CK1a inhibition by treating these mice with “cKit+ leukemia progenitors, highly enriched in leukemic stem cells (LSCs)” which is specific for attacking these cells (Minze et al., 2018). Researchers found that CK1a inhibitors selectively affected leukemia cells: indicating that some of the treated mice would survive the treatment, but not all. Through looking at leukemic drug A51 and A86 overall had the greatest progressive rate for binding affinity in CDK 7/9. From Model 2C, A51 was shown to be an excellent pathway for increasing p53, caspase 3, and gamma H2AX which makes this an okay drug to use. Although, A14 had the most effective binding affinity rate for CK1a, CDK7, and CDK9, which allowed A14 to work more effectively by having an increase stability of cells without breakage since CK1a was present and gamma H2AX was not. Moreover, A64 was shown to be the weakest drug to be used.

Furthermore, in model 1A, the cell number chart showed that when the researchers turn off CK1a inhibitors there was a better chance of lowering leukemic cells than there was when CK1a and p53 were turned off. The demonstration was illustrated by the red circle in comparison to the blue squares and purple triangles which represented the control group. For model 2A, the Annexin V chart, CK1a was shown to bind well with A86 than the other drugs at a quicker and higher rate for apoptosis in these leukemic cells within the mice. In Model 3B of the peripheral blood sample (PB), it showed that the leukemic bone marrow cells were at least lowered by 5 to 10 percent after about 6 hours after being treated versus no treatment and in Model 2E it showed how A51 eliminated a significant amount of leukemia in the bone marrow.

After giving the mice one dose of the cKit+ treatment for 18 hours, signs of leukemia in certain organ tissue after 5 to 6 hours, according to researchers, were mostly gone. Treatment showed improvements within their spleen, liver, bone marrow, and blood. Although all the mice did not have a successful survival rate, the drug A14 showed favorable health signs because the treatment did not affect major organs such as the heart, lungs, and intestines while being used as a short-term treatment. A51 treatment seemed to be better because it was able to lower leukemic cells in the bone marrow better than A86, A14, and other drugs because it stabilized the leukemic cells and killed them off by using donor mice bone marrow to save the AML mice as shown by the survival rate in Model 3G. I believe the researchers accomplished their main goal of finding a drug that could ultimately save human lives from AML leukemia while also finding a drug that co-targeted CK1a. I would recommend that the drug A51, A14, and A86 be used retrospectively among individuals as all three could be beneficial. Although, doing a bone marrow transplant with using treatment A51 would be more highly effective.

References

Graf, F., Wuest, F., and Pietzsch, J. (2011). Cyclin-Dependent Kinases (Cdk) as targets for cancer therapy and imaging. In Advances in cancer therapy (InTech).

(2018). Leukemia. In Mayo Clinic diseases and conditions (Mayo Foundation for Medical Education and Research).

Minzel, W., Venkatachalam, A., Fink, A., Pikarsky, E., Snir-Alkalay, I., and Ben-Neriah, Y. (2018). Small Molecules Co-targeting CKIa and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. (In Cell Press).

Samarasinghe, B. (2013). Hallmarks of Cancer 3: Evading Apoptosis. In Scientific American Guest Blog (Springer Nature America, Inc.).