Dr Emmanuelle Passegué, PhD, of the University of California, San Francisco, and his team have identified a gene that controls the rapid production and differentiation of the stem cells that produce all blood cell types—a discovery that could eventually open the door to more streamlined treatments for leukemia and other blood cancers, in which blood cells proliferate out of control.
Additionally, in investigating the mechanisms of this gene, the scientists uncovered evidence that could lead to a protocol for bone marrow transplants that could boost the chance of a cure in some patients.
The path breaking research demonstrates that the JunB gene is at the center of a complex network of molecular and environmental signals that regulate the proliferation and differentiation of hematopoietic stem cells, the multipotent, self-renewing cells that give rise to all blood cell types.
The study published on April 7, 2009, in the journal Cancer Cell. Passegué’s team studied the behavior of JunB-deficient HSCs in both the culture dish and when transplanted into mice. In every case in which engraftment of the HSCs occurred in the mice, they noted a progressive expansion of the myeloidlineage, which constitutes a type of mature white blood cell that fights infection. This expansion led by 6 to 12 months post-transplantation to the development of a myeloproliferative disease, which can evolve to leukemia. The finding indicated that the proliferating JunB-deficient HSCs causes leukemia.
In a simple understandable way, like traffic lights, which limit speed, direct the flow of vehicles and prevent accidents, JunB curtails both the rate at which HSCs are proliferating and the rate of differentiation toward the myeloid lineage that ultimately results in leukemia.
It is suggested that without JunB, HSCs lose their ability to respond to signals from the protein receptors Notch and TGF-beta, which reside on the cells’ surface and play critical roles in determining cell fate.
“With the knowledge of this mechanism, we may be able to determine the difference between normal HSCs and leukemic stem cells in gene regulatory networks. This could allow us to develop more targeted therapies. These kinds of therapeutic applications are still down the road, but they can happen very quickly in the blood/leukemia field,” says Passegué.
This study represents a turnabout from other research, which has demonstrated that mutated HSC, that cause leukemia, burn out at a faster rate than normal HSCs. In contrast, this study shows that JunB does not affect the cells’ potential for unlimited self-renewal.
This finding may have important ramifications for patients undergoing bone marrow transplants, for leukemia, lymphoma, multiple myeloma and certain cancers.
“Currently, patients undergoing bone marrow transplants may not be getting enough of the quiescent transplanted HSCs that are optimal for successful engraftment,” suggests Passegué. Probably using a highly purified HSC population down the line could be more beneficial.