UW Research Team Identifies Mechanism Driving Leukemia Development
Madison, Wisconsin - In another step toward unraveling the causes of serious blood disorders, a UW-Madison research team has identified how a genetic network in certain blood cells can be disrupted and go on to promote the development of certain forms of leukemia.
The new findings were published in the August edition of the scientific journal Cell Reports. Dr. Emery H. Bresnick, Kellett Professor of Cell and Regenerative Biology at the UW School of Medicine and Public Health, and director of the UW-Madison Blood Research Program, led the research team.
Dr. Koichi R. Katsumura (assistant scientist in the Bresnick group and first author of the paper) led the experimental effort, while Dr. Irene Ong (from the UW Carbone Cancer Center) spearheaded the cancer informatics effort.
Acute myeloid leukemia (AML) is a serious, often fatal disease, with about 20,000 new cases diagnosed every year. It arises when myeloid cells, produced in the bone marrow, proliferate abnormally. The specific mechanisms that cause the disease, however, are not fully understood. In a normal context, myeloid cells go on to become various components of blood.
While other gene mutations are also known to be involved, Bresnick and colleagues were looking at the role of GATA-2, a gene identified as a “master regulator” of the blood-cell production process. Mutations in GATA-2 cause a primary immune-deficiency syndrome that can progress to AML.
It is known that the activity of GATA-2 must be kept within a specific range; too much expression of the gene correlates with a poor prognosis for adults and children with acute myeloid leukemia (AML), while too little is also linked to the disease.
In this study, the scientists were trying to determine how the GATA-2 network is related to the development of these blood disorders. Through a series of experiments, they discovered an intricate mechanism that sets up a growth circuit in AML cells. The circuit begins when Ras, another gene often involved in malignancies, produces signals that stimulate a chemical process called phosphorylation in GATA-2.
That in turn increases the ability of GATA-2 to control the activity of genes (transcription - the first step in gene expression) in AML cells, and these genes generate cell-signaling proteins that control the proliferation of these cells.
Description of the growth-promoting circuit might point the way to better treatments, not just for acute myeloid leukemia, but for other cancers in which GATA-2 is implicated: non-small cell lung cancer, prostate cancer and glioma.
Bresnick says the next step in the work includes analyzing the contribution of the new circuit to AML cell growth in mouse models and in human leukemia, as a prelude to forging clinical and translational strategies to improve therapeutic options for AML, which are sorely needed.
The research was supported by the National Institutes of Health, Midwest Athletes against Childhood Cancer, and the Carbone Cancer Center.
Date Published: 08/18/2016