Graduate student Zhen Zhao, postdoctoral researcher Johannes Zuber, M.D., along with Lowe and others, hypothesized that loss of the p53 protein could impair the programmed cell fate and mortality of myeloid progenitors. "Although myeloid progenitors and their differentiated progeny normally lack self-renewal capabilities," explains Zhao, "these cells apparently acquire this ability during the course of leukemia development. How this happens is what we set out to discover."
Zhao and colleagues knew that mutations in Kras and other genes in the Ras signaling pathway can trigger replication stress in immature blood cells, in some instances calling p53 into action. That protein possesses a range of biological activities that are thought to contribute to its role in tumor suppression, including the ability to induce a cell to commit suicide (apoptosis) or to enter a quiescent state in which it can no longer multiply (senescence). When the p53 protein is missing or inactive, for instance due to a mutation in the gene that encodes it, a potentially vital element in a cell's "braking" system is disabled. Indeed, "mutational disruption of the p53 network is thought to occur in virtually all aggressive end-stage cancers," notes Zhao, although mutations are seen in only 10%-15% of AML cases at diagnosis. Those tend to be the cases most resistant to therapy and most likely to be lethal.
Using so-called mosaic mouse models, the Lowe lab recently demonstrated that p53 mutations could specifically confer resistance to chemotherapeutic agents used to treat AML in human patients. Zhao, Zuber and colleagues took advantage of these genetically hybrid mice and a technology called RNA interference, or RNAi. Using a short-hairpin RNA molecule, they inactivated the p53 gene in hematopoietic cells that also had mutations that made Kras oncogenic. Myeloid precursor cells with only the Kras mutation are proliferative, but not sel
|Contact: Peter Tarr|
Cold Spring Harbor Laboratory