Leukemia and epigenetics
Epigenetic analysis will help in the fight against leukemia
Lina Medvedeva, XX2 century
Recently developed by researchers at the Cornell University School of Medicine (Weill Cornell Medicine) and the New York Genome Center (NYGC), a set of tools allows you to track the molecular evolution of cancer. With its help, scientists are able to better understand how oncological diseases arise and spread in the body and how cancer reacts to various treatment methods.
The approach described in articles in Nature and Nature Communications allows isolating individual cancer cells taken from patients and mapping epigenetic labels on cell chromosomes. Epigenetic tags are chemical tags on DNA or DNA–supporting proteins (they are called histones and help to control which genes in a cell are turned on and which are turned off). In fact, they program what the cell does. Previous studies have shown that epigenetic changes in cells are to some extent the cause of cancer. However, relatively little research has been done in this area. Much more attention is paid to genetic mutations that cause cancer.
In a new study, scientists have identified a set of epigenetic labels, "epigenomes", thousands of cancer cells taken from patients with chronic lymphocytic leukemia. This slowly progressing malignant neoplasm affects B-lymphocytes. Scientists analyzed a huge array of epigenomic data to show how patients developed cancer at the epigenetic level and how they reacted to standard treatment with ibrutinib.
"With the help of epigenetic information, we were able to track the line of development of cancer cells and the evolution of their populations with high accuracy, which could not have been done earlier on human samples," he said. Dr. Dan Landau, Associate Professor of the Department of Medicine and an employee of the Oncology Center. Sandra and Edward Meyer Cancer Center at Cornell University School of Medicine. "Such an analysis can give us an idea of how different types of cancer adapt to drug treatment."
For the study, which resulted in an article published in Nature, Dr. Landau and his colleagues used a methylation technique to apply epigenetic labels. It was applied to more than 800 normal B-lymphocytes of six healthy people and more than 1800 cancer cells of 12 patients with chronic lymphocytic leukemia. The scientists found that in the cell populations of patients with leukemia, the rate of epimutation, that is, the average change in the epigenome with each cell division, was abnormally and equally high. This has led to a significant diversity of epigenetic patterns among cells.
Previously, Dr. Landau and other researchers have shown how cancer is diversified at the genetic level so that different tumor cells contain different sets of mutations. "Such a huge diversity in each population of cancer cells means that in each case we are dealing with thousands of cancer variants, and not with a single object. All these differences increase the potential of cancer adaptation to drug therapy," says Dr. Landau. "We have expanded this concept by showing that there is epigenetic diversity."
Scientists were able to analyze epigenomic data, they traced the line of each leukemia cell to its source of origin and showed how it developed during the disease. Scientists classified leukemia cells into various groups, "phylogenetic branches", closely related cells based on their epigenomic models and showed that some of them were sensitive to treatment with ibrutinib, and some were not. A similar analysis is planned to be carried out in further studies to find out how effectively the drug or combination of drugs work against this cancer. This could lead to more effective ways to monitor cancer progression and detect drug resistance.
In a study published in Nature Communications, Landau and his colleagues showed that they can apply epigenetic tags, histone modifications, in addition to methylation, to the DNA of a patient's leukemia cells with an accuracy of one cell. DNA is packed into chromosomes, partially wrapped on histone proteins. Small chemical changes in histones can weaken or tighten this coil at various points, which suppresses or resolves the activity of genes. A study conducted in collaboration with the laboratory of Dr. Omar Abdel-Wahab at Memorial Sloan Kettering Cancer Center showed that leukemia cell populations, along with other epigenetic labels, diversify sets of histone modifications.
Both studies have confirmed that, at the epigenetic level, leukemia cell populations lose the order observed in populations of healthy B-lymphocytes. "Normal human cells are programmed to function precisely within a multicellular organism," says Dr. Landau. – Cancer cells turn into something more than a single-celled form of life, for example, bacteria. In bacteria, you can also see a diversifying trend that makes the population more stable."
Both studies have shown that the approach developed by Dr. Landau and his colleagues can be used to determine not only different types of epigenetic information, but also the genetic DNA sequence, as well as gene expression models, and in individual cells.
"Understanding the epigenetic changes occurring in individual cells will allow us to better understand how cells develop resistance to our treatments and how this can be prevented," said Dr. Richard Furman, co–author of the paper. "This information is important in order to help patients with leukemia achieve a normal life expectancy."
"We hope to use this opportunity to obtain multi–level information from individual cells in order to understand all the molecular relationships that determine the development of cancer and its resistance to therapy, as well as ways to prevent resistance," said Dr. Landau.
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