Blood cell formation, known as hematopoiesis, begins with a hematopoietic stem cell (HSC), which can either "self-renew" and make more copies of itself or differentiate into either red blood cells, various types of white blood cells, or platelets. The genes that control proliferation and differentiation have been difficult to study using traditional gene disruption methods because loss of genes thought to be critical for this process often results in embryonic death, making it impossible to study the role of the gene of interest in mature animals.
Dr. Michael P. Cooke and colleagues from the Genomics Institute of the Novartis Research Foundation in San Diego found a way around this problem. The researchers used random mutagenesis and screening to find animals with hematopoiesis defects, and they used genetics to identify the causative gene. One line mapped to a mutation in the gene c-Myb, which has a known role in regulation of blood formation.
Interestingly, they found that c-Myb is not required for every step of hematopoiesis or for every type of blood cell. Instead, c-Myb is critical for very distinct steps in the formation of specific types of blood cells. Most surprisingly, the c-Myb mutants also had a dramatic increase in the total number of HSCs, suggesting that part of the normal function of c-Myb is to hold HSC multiplication in check.
These data suggest that c-Myb is a key regulator of hematopoiesis and acts at many distinct points to control HSCs. "It is remarkable that a single transcription factor controls the diverse processes of self-renewal, proliferation, and differentiation" says Dr. Cooke. "The next challenge is to understand how c-Myb controls HSC numbers and use this information to develop compounds that can regulate stem cell proliferation and differentiation. The ability to influence stem cell fate decisions would be expected to have a major impact on the field of stem cell therapy and to provide important in vitro model systems for the identification of genes and compounds that can be used to regulate the process of stem cell differentiation."
Mark L. Sandberg, Susan E. Sutton, Mathew T. Pletcher, Tim Wiltshire, Lisa M. Tarantino, John B. Hogenesch, and Michael P. Cooke: "c-Myb and p300 Regulate Hematopoietic Stem Cell Proliferation and Differentiation"
The other members of the research team include Mark L. Sandberg, Susan E. Sutton, Mathew T. Pletcher, Tim Wiltshire, Lisa M. Tarantino, John B. Hogenesch, and Michael P. Cooke of the Genomics Institute of the Novartis Research Foundation.
Publishing in Developmental Cell, Volume 8, Number 2, February 2005, pages 153-166. www.developmentalcell.com/