Leukemia is an interesting topic because there are many different types of it, but scientists still haven’t figured out the exact causes of it. They think it develops from environmental and genetic factors. Some forms of Leukemia occur mostly in adults and some are more common in children. It affects more adults, its more common in men, and more common in whites than African Americans. Leukemia is cancer of the body’s blood forming tissues, which includes the lymphatic system and bone marrow. The bone marrow produces abnormal white blood cells that don’t function properly. It’s exciting to learn about new drugs that could have potential and give hope to these patients.
The purpose of this study was to find a way to improve AML therapy because over the past 40 years there hasn’t been any major progress in the therapy of AML. Acute myeloid leukemia(AML) is a type of blood cancer that typically begins in cells that turn into white blood cells. It starts in the bone marrow which is the softer inner parts of the bones. The bone marrow cells don’t mature how they should. They are referred to as blast cells and these immature cells keep building up. In this study they used Small Molecules Co-targeting CKIa and the Transcriptional Kinases CDK7/9 to control AML.
The study was conducted using various methods. The methods include: Development of small molecule CKI inhibitors (cotargeting CKIa and CDK7/9), Kd determination, AML mouse models and inhibitor treatment, In vivo and ex vivo treatments, Crystallography studies ( which provide structural basis for distinct kinase co-targeting), Ex vivo assays, CFU assay, Histology and immunohistochemistry (IHC), Blood Smear, Blood analysis, Flow cytometry, Antibodies used for HSC staining, Human shRNA sequences, Western blot analysis, RT-qPCR analysis, qPCR primers used in this study, Chromatin Immunoprecipitation, ChIP-seq data processing, Chemical synthesis procedures quantification and statistical analysis, data and software availability.
The two inhibitors that showed the most promise was A51 and A86. They were the two best inhibitors because they lead to increased apoptosis (cell death) and decreased proliferation (in numbers) of AML cells. There was a loss in phosphorlyated serine 45 on b-Catenin (p45-b-Cat) when cells were treated with A51 and CK1a was present. A51 and A86 reduce the effects of CDK7. The effect it should have on transcription is to inhibit. The effect it should have on the cell cycle is to decrease proliferation. The effect it should have on Leukemia is to kill. A51 and A86 reduce the effects of CDK9. The effect it should have on transcription is to inhibit. The effect it should have on the cell cycle is to decrease proliferation. The effect it should have on Leukemia is to kill. A51 increases gamma H2AX, Caspase 3, and p53. A51 increases b -Catenin and it has the strongest effect on b-Cat stability. A51 made signs of AML better by improving the appearance. When mice were treated with A51, the number of AML cells in the bone marrow decreased significantly. Blood, bone marrow, spleen, and liver improved in mice 16 hours after a single treatment of A51. Based on the results it should improve the mice lifespan. When treated with the drugs some of the mice still died, but half of the mice treated with the drugs lived longer. All mice given “cured” bone marrow by A51 survived. A51 and A86 had the strongest effects on gamma H2AX, Caspase 3, and p53. The most reasonable outcome when cells are treated with A51 and A86 is that they restore detection of DNA damage and they restore apoptosis. Originally, I predicted A14 would have the strongest effect on CK1a based on binding affinity, but the actual binding didn’t show that. For CDK7 and CDK9 I predicted A86 and A51 to have the strongest effects based on their binding affinity and this was correct.
The results were good compared to the author’s goals. The small molecule inhibitors that they developed were successful. I wouldn’t say that the drugs 100% cure AML because some of the mice who got the inhibitors still died. However, I think the inhibitors cured AML for the surviving mice and that AML couldn’t be transmitted to the healthy mice. I do recommend these drugs for clinic testing on humans because after looking at these results they have potential.
Citations
Mayo Clinic. (2018). Leukemia – Symptoms and causes. [online] Available at: https://www.mayoclinic.org/diseases-conditions/leukemia/symptoms-causes/syc-20374373 [Accessed 3 Dec. 2018].
Minzel, W., Venkatachalam, A., Fink, A., Hung, E., Brachya, G., Burstain, I., Shaham, M., Rivlin, A., Omer, I., Zinger, A, et al. (2018). Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. [online]
WebMD. (2018). Leukemia: Symptoms, Causes, Treatment. [online] Available at: https://www.webmd.com/cancer/lymphoma/understanding-leukemia-basics#1 [Accessed 3 Dec. 2018].
WebMD. (2018). What Is Acute Myeloid Leukemia? What Causes It?. [online] Available at: https://www.webmd.com/cancer/lymphoma/acute-myeloid-leukemia-symptoms-treatments [Accessed 3 Dec. 2018].