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DNA mutations that lead to a change in the modification of ribonucleic acid molecules, to remove parts of the DNA that are not translated to proteins and mutations in the modulation of DNA and histone proteins without changing the DNA sequence, work together to drive the development of myeloid leukemia, a cancer of the blood.
Mutations in the splicing of mRNA, the ribonucleic acid molecules that copies genetic information from DNA and translates it into a polypeptide chain and those in the apparatus that modulates DNA and its associated proteins without changing the DNA sequence have both been characterized in leukemia a cancer of the blood (Kim et al. 2015). How the cooccurrence of these mutations can impact the progress of leukemia is not well characterized in research literature (Yoshimi et al. 2019). Understanding the interaction between two or more mutations in the same cancer type sheds light on the causes of differential response to cancer therapies and varied survival rates (Ilagan et al. 2015). Tracing cancer causing mutations, and their developmental mechanisms in cancer development helps us to detect the mutations earlier through genetic testing raising the chances of finding a viable form of treatment for the cancer. Projects like the Pan-Cancer Analysis of Whole Genomes (PGAWG) are part of the growing attempts to locate and characterize most if not all cancer causing mutations (Gerstung et al. 2020) and (Yoshimi et al. 2019) in their paper reinforce prioritizing the impact of cooccurrence of mutations in a single cancer type.
Yoshimi, et al. analyzed 179 patients with myeloid leukemia, and identified mutations in IDH2 and SRSF2 genes. Myeloid leukemia is a cancer type of the blood and bone marrow that is characterized by presence of excessive abnormal white blood cells. These identified mutations hinder immature blood cells in the bone marrow from developing into healthy cells that can enter the blood stream and perform varied functions like fighting off infection. Researchers observed that 47% of the patients with a mutation that is a change in the DNA sequence of the SRSF2 gene had the IDH2 mutation and 56% of the patients with the IDH2 mutation also had a mutation in SRSF2 showing that these two mutation occur together more frequently and the double mutant carrying patients resulted in the shortest overall survival rate.
Yoshimi, et al. confirm the cooperativity of mutations in IDH2 and SRSF2 genes in defining and worsening leukemia in transgenic mice. The symptoms of leukemia were more pronounced in individuals with both mutations than those carrying either one of the mutations occurring alone. Changes in both DNA sequences were followed by more extreme characteristics of myeloid leukemia like an increased ability of cells to form clones of themselves, having very large red blood cells than normal, lowered numbers of cells that help with blood clotting when one is injured (platelets), and the presence of underdeveloped immune cells in the blood stream. Researchers explain that the these identified mutations also occur in other cancer types as well as myeloid leukemia which they characterized.
Yoshimi, et al. also show that IDH2 and SRSF2 mutations led to lowered expression of the protein INTS3 and other proteins that are part of the machinery that modifies messenger ribonucleic acid molecules before they are used to translate DNA information into proteins. A process called methylation, that is done on a DNA molecule to reduce how much of the DNA is made into protein was driven by the presence of the SRSF2 mutation and enhanced by the presence of IDH2 mutations and together, mutations were stopping the action of the protein that creates messenger ribonucleic acid molecules. Overall the researchers show that two mutations work together in disrupting the expression of the INTS3 protein that has been shown to be involved in DNA repair before and when cells are altered to over express this proteins, leukemia development was decelerated.
Researchers did not follow the trajectory to explore the mechanisms that are affected by the loss of INTS3 and other similarly acting proteins and how these mechanisms lead to the development of myeloid leukemia. We know that the mutations lead to the development of myeloid leukemia as shown in their data with transgenic mice carrying both mutations but it can only be inferred from the known and mentioned signs of leukemia that mutations work together to hinder cells in the bone marrow from fully maturing and also enhance their ability to form cancerous clones. Follow up studies of this paper can explore the roles of proteins identified to be lost in IDH2 and SRSF2 mutants and how their absence directs development of leukemia.
In their study, Yoshimi, et al. provide ample evidence characterizing how these two mutations that are part of different processes of DNA manipulation affect each other to cause a cancer type that is known to spread very fast. Studies that look at the interaction of cancer causing genes are vital to our understanding of the factors that enhance the ability of cancerous cells to clone and spread to other tissues in the body. This study also adds to the existing knowledge of genes that cause cancers by identifying a critical aspect of myeloid leukemias that can allow better genetic testing tools that can help us identify how high the risk is for certain individuals to develop cancer.
Tanatswa Muchenje is a Junior Biology major at Davidson College. Contact her at tamuchenje@davidson.edu
References
Yoshimi, A., L. Kuan-ting, D. H. Wiseman, M. A. Rahman, P. Alessandro et al., 2019. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature 574, 273-277
https://doi.org/10.1038/s41586-019-1618-0
Gerstung, M., C. Jolly, I. Leshchiner, S. C. Dentro, S. Gonzalez et al., 2020. The evolutionary history of 2,658 cancers. Nature 578, 122-128
https://doi.org/10.1038/s41586-019-1907-7
Ilagan, J. O., A. Ramakrishnan., B. Hayes, M. E. Murphy., A. S. Zebari et al., 2015. U2AF1 mutations alter splice site recognition in hematological malignancies. Genome research, 25(1), 14–26.
https://doi.org/10.1101/gr.181016.114
Kim, E., J. O. Ilagan, Y. Liang., G. M. Daubner, S. C. Lee et al., 2015. SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer cell, 27(5), 617–630.
https://doi.org/10.1016/j.ccell.2015.04.006
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