The HSCI Blood Program seeks to define the mechanisms that turn blood stem cell self-renewal on and off. Turning on self-renewal is critical for regenerating damaged tissues; turning off self-renewal is critical for stopping or slowing blood cancers like leukemia and lymphoma.
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Key Research Questions
The HSCI Blood Program employs the use of genetic screens, mouse models of disease, bioinformatics, and comparative cell analysis to answer the following questions:
- What are the specific molecular regulators of blood stem cell self-renewal?
- What common data sets and computational tools can be used to study the genes involved in self-renewal?
- Do stem cell systems share regulators across tissue type(s)?
- Can chemical screens for compounds to control self-renewal be developed?
Key Scientific Results
Scientific findings from the HSCI Blood Program include:
- Chemical screens led to the identification of an activator of blood stem cells in zebrafish. The compound yielded a 4-fold increase in the engrafting of treated bone marrow compared to controls. This compound, which was developed to improve adult cord blood transplants, recently passed Phase I clinical trials.
- During irradiation or chemotherapy, blood stem cells recover through the action of signaling pathways that are triggered by growth factors. The growth factors cause specific DNA-binding proteins to bind with blood genes. This binding leads to activation of the blood genes and helps the recovery process. This basic scientific discovery could hasten the search for small molecules that enhance self-renewal during marrow or cord blood transplantation.
- The same epigenetic changes, modification of cellular DNA by methylation, are present during normal blood cell formation and the development of leukemia. However, DNA methylation or unmethylation occurs at different steps in normal versus cancerous blood stem cells. These findings suggest a favorable therapeutic index for the use of DNA methylation inhibitors in leukemia.