Mark G. Frattini, MD, PhD
Yesterday, Dr. Leonard Zon of Children’s Hospital and Dana-Farber Cancer Institute delivered the E. Donnall Thomas Lecture titled “Blood Stem Cell Self-Renewal and Differentiation – Lessons from Embryonic Development.” Dr. Zon began his lecture outlining that hematopoietic stem cells are derived during embryogenesis and can either self-renew or differentiate into all cell types seen in the peripheral blood. Research done during his postdoctoral career with Dr. Stuart Orkin resulted in the cloning of the GATA-1 gene that was found to be the master regulator of the red blood cell lineage. After spending some time using the frog Xenopus laevis as a model system, he was quickly convinced to switch to the zebrafish. Being a small vertebrate, it was likely that the gene sets discovered in the zebrafish would be similar to those regulating the same process in humans. He outlined several advantages of the zebrafish system stating that “the zebrafish embryos are transparent and circulating blood can be seen at 23 hours after fertilization. We have made a number of transgenic fish that target fluorescent proteins to blood cell lineages. Each mother has 100 to 200 babies per week and that facilitates genetic screens.” In addition, there is knockdown technology available using morpholinos. Although the technology was available to make mutants in the zebrafish, there was a need to obtain the genome sequence to allow for cloning of the mutants. Dr. Zon was instrumental in getting this done in collaboration with the National Institutes of Health and the Sanger Center.
Using the zebrafish system, his group discovered the function of several of the mutants including ferroportin that functions as the iron transporter that carries maternal iron to the developing baby, the Cdx-Hox pathway that controls hematopoiesis, and TIFα that links transcription elongation to hematopoietic DNA-binding proteins and the control of cell fate in different tissues.
In pioneering work from his laboratory, Dr. Zon discovered that dimethyl-prostaglandin E2 (dmPGE2) can stimulate hematopoietic stem cells not only in zebrafish embryos, but also in experiments with mouse bone marrow and in immune-compromised mice using human cord blood cells. The results of these experiments showed that the frequency of stem cell engraftment can be increased 4-fold after treatment with dmPGE2. These findings have recently been translated to a phase I clinical trial using double umbilical cord blood stem cell transplantation, where one cord blood unit is left untreated and the second is treated with dmPGE2 in order to investigate the effects on time to engraftment and bone marrow chimerism. The results of this trial are ongoing.
Dr. Zon went on to demonstrate in a series of elegant experiments the interaction of both the PGE2 and Wnt pathways in the regulation of not only stem cell homing but also self-renewal. Lastly, he outlined the development of the first successful zebrafish marrow transplant model in which chemical screens can now be performed to identify small molecules that can affect stem cell biology.
“I was very happy to win the E. Donnall Thomas Prize. First, I have a great admiration for Don. He started his career working on the dog, and perfecting marrow transplantation, and then later applied the work to humans. Second, this is such a great honor, and it validates the approach that we took using the zebrafish to find interesting genes and pathways that regulate blood development,” Dr. Zon said.
“In my career, I have used the zebrafish as a model, and hope to have an impact on human health and disease.” He has.
Dr. Frattini indicated no relevant conflicts of interest.