Generation of a humanized mouse xenotransplant model of myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are diseases of the blood and bone marrow. MDS originate when a stem cell, from which all other blood cells originate, becomes mutated and then overgrows and crowds out other cells. This results in reduced numbers of red cells (anemia), white cells (leukopenia) and platelets (thrombocytopenia) circulating in the blood. As the disease progresses, bone marrow may completely fail to produce normal cells, and the myelodysplastic stem cell may develop into cancer, Acute myeloid leukemia (AML). The exact molecular causes for MDS are unknown; however, a common feature of MDS is chromosomal abnormality, the loss of the long arm (q) of the chromosome 5 being one of the most common in a subtype of MDS called 5q- syndrome. This lost region of 5q likely harbors several important genes, which may prevent MDS.

Dr. Joanna Wegrzyn Woltosz's research project will decipher the molecular mechanism of the disease and identify targets of a new drug (lenalidomide) currently used in MDS treatment. She is studying two important factors that are located on the 5q arm and are involved in the development of MDS (1) the RPS14 gene, which is thought to be responsible for the anemia seen in MDS patients, and (2) microRNAs, whose loss allows the abnormal MDS stem cells to survive and grow more than the other bone marrow cells. Since lenalidomide reverses symptoms resulting from loss of the microRNAs, she will also study whether lenalidomide increases the expression of these microRNAs. Currently, the only treatment for MDS is high-dose chemotherapy with stem cell transplantation, which is risky and challenging for patients to endure.

The information Dr. Wegrzyn Woltosz expects to obtain from this study will not only help to better understand the molecular mechanism underlying MDS, but will suggest novel steps towards the development of better therapies that will improve treatment and quality of life and increase survival for MDS patients.