UW Researchers Identify Gene Mutation that Causes Subset of Leukemia
Madison, Wisconsin - Researchers at the University of Wisconsin-Madison have revealed the function of a small chromosome segment directly responsible for a subset of myeloid leukemias.
Knowing the origin could give researchers and clinicians a way to specifically treat the cause of the disease, rather than using general therapies that target symptoms instead of the source.
The study, published in Science Advances on Friday (Sept. 4), distinguishes the normal function of a non-coding DNA element from its ability to promote leukemia when it is relocated away from its normal site on the chromosome due to a mutation.
In patients harboring the relocated DNA element, previous work has shown the mutation causes the expression patterns of two important regulators of blood cells to change; while the original gene loses function, the misplaced DNA element stimulates the overexpression of the new neighboring gene.
By deleting the non-coding DNA element from the genome of mice, the team of researchers determined how the non-coding DNA element contributed to the function of the gene where it normally resides — next to GATA-2.
The research was led by Emery Bresnick, Kellett Professor of Cell and Regenerative Biology, and Kirby Johnson, a senior scientist at the UW School of Medicine and Public Health, and involved a diverse team of campus experts including Jing Zhang (McArdle Laboratory for Cancer Research and co-Director of the UW-Madison Blood Research Program), Colin Dewey (Department of Biostatistics and Medical Informatics) and David Yang (Department of Pathology and Laboratory Medicine).
GATA-2 is indispensable for blood cell production, regulating multiple steps in the process including the generation and activity of hematopoietic stem cells (HSCs) that are responsible for producing the different types of blood and immune cells needed to maintain a healthy day-to-day balance in the body and to defend against life-threatening infections.
Mutations that increase or decrease the GATA-2 levels in blood cells increase the likelihood of developing myeloid leukemia by disrupting the normal process of blood cell development. Removal of this particular non-coding DNA element discovered in the Bresnick lab disrupts the GATA-2 gene in a subset of blood cells called myeloid cells, a group of cells that develop into a variety of different blood cell types.
Without the proper levels of the GATA-2 protein, the production of certain immune cells and red blood cells is altered and often halted at a stage before cells are ready to properly function. This “myeloid blockade” is a common feature in leukemia.
Current therapies and treatments for acute myeloid leukemia have produced a five-year survival rate ranging widely from 15 to 70 percent depending on the specific subtype. There is a critical need to develop new therapeutic approaches, as well as biomarkers to permit “personalized medicine,” to gauge whether a given therapy will be effective in a particular patient.
Understanding the normal genetic mechanisms and how they are disrupted, which can cause or be caused by specific diseases, provides invaluable insight and direction for treatment.
The study was supported by National Institutes of Health grants DK68634 and DK50107, CA152108 and HL113066, and U01 HG007019, and Cancer Center Support Grant P30 CA014520 obtained by multiple study authors.
Date Published: 09/08/2015