Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders and the most common cause of acquired bone marrow failure in adults. There is accumulating data that indicates mutations in specific genes are very important in the development of MDS. Moreover, we and others have recently shown that these genetic abnormalities can be reliably utilized to predict the severity and clinical course of disease in patients with MDS. Interestingly, several of the most common mutations identified in MDS patients are in genes that encode for enzymes and other proteins that regulate the state of the epigenome. The epigenome consists of the chemical modifications added to DNA bases and modifications of the histone proteins to which DNA is bound. Mutations in such epigenetic-modifying genes are important in MDS patients and include mutations in the genes TET2, ASXL1, EZH2, and DNMT3a.

In this proposal, we hypothesize that frequent mutations in these genes will serve to help us in (a) understanding the development of MDS further through the creation of genetically engineered mouse models involving these genes and (b) developing new therapies for MDS patients. In fact, we have recently published that mice engineered to have deletion of Tet2 in their blood-forming stem cells develop a disease that has features of MDS combined with myeloproliferative disorders. Moreover, we have very exciting preliminary data that mice with deletion of Asxl1 in their blood-forming cells develop a disease very similar to human MDS. We are now in the process of creating additional mouse models with combinations of Tet2, Asxl1, and Ezh2 loss to mimic the combinations of genetic abnormalities found in many patients with MDS. This is a critical undertaking because there are currently very few mouse models of MDS, and those that exist are not based on the genetic abnormalities that are common to most MDS patients. We believe that these mice will serve as an essential resource to understanding the biology of MDS and developing new therapies.

We propose to utilize our existing and new mouse models of MDS to identify how genetic abnormalities common to MDS patients affect the response to drugs being administered to MDS patients currently. Equally important, we also propose to utilize these mouse models to identify new therapies for patients with MDS. Indeed, we have very promising preliminary data that indicates blood cells with TET2 loss may be particularly sensitive to HDAC inhibitors, a class of drugs currently being tested in many cancer patients. This observation could have tremendous importance to patients with MDS given that mutations in TET2 are currently the most common genetic abnormality in MDS patients.

In the last part of this proposal, we propose to identify new genetic abnormalities in specific subsets of MDS patients with the worst prognosis using state-of-the-art technologies. Our lab has significant expertise in gene discovery efforts, and we have recently described several new genetic abnormalities in patients with blood cancers related to MDS.

The work described in this project encapsulates my long-term career goal to discover underlying genetic causes of acquired bone marrow failure in hopes of developing new therapies. Awards such as this Department of Defense Postdoctoral Fellowship Award would be a tremendous aid towards my hopes of establishing an independent career as a physician-scientist.