Ross Levine, M.D.
2021 Funding recipient
Identification of novel therapies that can suppress clonal expansion and evolution to MDS
Discovery Research Grant 2021
Myelodysplastic syndrome (MDS) is a disease characterized by reduced levels of red blood cells, platelets, and leukocytes which are involved in establishing an immune response. MDS patients have an increased likelihood to develop acute myeloid leukemia (AML), a fatal disease characterized by increased stem cells and a loss of normal blood development. While FDA approved therapies exist for MDS or for AML secondary to MDS, there are few curative treatments.
MDS increases in frequency with aging, and occurs through stepwise acquisition of genetic mutations in blood stem cells. DNA-sequencing studies have identified a catalogue of mutations that may offer clues into how MDS develops, including recurrent mutations in DNMT3A, TET2, and ASXL1. Mutations in these genes, and others, are thought to increase the abundance of stem cells, at the expense of producing less mature cells that maintain normal blood function. Moreover, it is now appreciated that there are many clinically healthy subjects who have mutations in these MDS genes in their stem cells without having overt symptoms or blood count alterations. This condition is called clonal hematopoiesis (CH), and patients with CH have a markedly increased risk of developing MDS/AML and an increased risk of age-associated malignant and non-malignant diseases. Notably, as many as 10-20% of healthy subjects 60 years and older have CH and an increased risk of MDS, such that it represents a common MDS precursor state and a possible opportunity for therapeutic intervention.
However, it remains unclear the exact molecular mechanisms of how these mutations elicit these effects, and whether they cause stem cells to grow more rapidly, die less frequently, or differentiate to mature blood cells at different rates or biases. Furthermore, it remains unclear whether we can selectively target mutated stem cells in an effort to prevent/intercept MDS development. Our research utilizes genetic mouse models to faithfully mimic human CH/MDS and to identify and test novel therapeutic approaches aimed to prevent/attenuate this disease. In these models, we are able to specifically mutate individual genes, such as DNMT3A and TET2, and to use these models to discover and validate specific therapeutic targets. We will use these models, in concert with patient samples, to uncover therapeutic targets for future drug development.
Our studies will grow mutant stem cells using a cell culture approach where we can mix normal and mutant stem cells over a layer of bone marrow endothelial cells, the constituent cells of the stem cell blood vessel niche. This culture system allows us to test a library of drug compounds for their ability to specifically target mutated stem cells. We believe this approach allows us to assess the functional capacity of mutant-MDS stem cells and identify which therapies show the greatest potential for translation into preclinical mouse studies and future clinical trials. Lastly, our research will take advantage of this culture system to perform genetic screens to identify new genes, which when mutated, specifically cause DNMT3A and TET2 mutant cells to die. We believe these approaches will inform fundamental insights into how MDS develops and offer new therapeutic opportunities to treat this disease.