A group of researchers from the University of Wisconsin School of Medicine and Public Health (SMPH) has unearthed a critical process in how healthy red blood cells are produced.
The research team, led by Dr. Emery Bresnick, discovered that two enhancers in the gene that generates the protein GATA-2 were responsible for regulating how this protein is produced in progenitor cells (early decendents of stem cells) that generate red blood cells, according to findings recently published in the journal Cell Reports. Bresnick is professor of cell and regenerative biology at the School of Medicine and Public Health and directs its Blood Research Program.
When GATA-2 is improperly produced, it can lead to leukemia and other blood disorders.
Bresnick’s research group previously discovered the two enhancers, -77 kb and +9.5 kb – named for their locations in the GATA-2 gene – in his research on how GATA-2 is regulated, how it functions to control blood cell development and how disruption of its function causes blood diseases.
This new study demonstrates the requirement of these two enhancers in the proper development of progenitor cells to red blood cells. When the two enhancers reside on the same allele, or segment, of DNA, a precursor cell called a megakaryocyte erythrocyte progenitor cell is created (MEP).
If mutations to the enhancers occur, or one of the enhancers is not on the same allele, it can lead to improper progenitor cell production, which could trigger the development of leukemia or other blood disorders.
“Mechanisms that control blood cell development from progenitors are crucial, since disruption of this process causes leukemia and other blood disorders,” Bresnick said.
To make this discovery, Bresnick and his team bred a set of mice with a mutation to the +9.5 kb enhancer with a set of mice that had a -77 kb enhancer mutation and examined the cell development of the embryos at various stages of growth.
This breeding process also produced evidence that -77 kb enhancer had an additional essential role to control the development of erythrocytes from a cell downstream of the MEP, called a burst-forming unit-erythroid, a committed erythroid precursor cell.
In addition to the laboratory work conducted by Bresnick’s team members Charu Mehta and Dr. Kirby Johnson, Dr. Irene Ong at the UW Carbone Cancer Center Shared Informatics Resource played an important role in analyzing complex genetic data derived from the mutant mice.
This recent discovery is the continuation of a long-term effort to understand how GATA-2 levels and activity are controlled, and how GATA-2 regulates the development and function of blood stem and progenitor cells, according to Bresnick.
“By unraveling the key mechanisms, this work could yield biomarkers and therapeutic targets that are not likely to emerge from conventional drug discovery approaches,” he said. “New therapeutic approaches are critically needed for GATA-2-dependent diseases like acute myeloid leukemia.”
The research was funded by grants from the National Institutes of Health and the UW Carbone Cancer Center.