PROJECT SUMMARY

In myelodysplastic syndrome (MDS), certain gene mutations cause the bone marrow to produce abnormal blood cells. Mutations in the ASXL1 gene are found in about 15% of patients with MDS. The presence of an ASXL1 mutation cuts average survival in half and increases the risk of progression to acute myeloid leukemia. Despite this, we do not have any treatments that specifically target mutant ASXL1. A major reason for this is that we do not understand how mutant ASXL1 causes the growth of MDS cells, making it difficult to develop new drugs to reverse these effects.

In our preliminary studies, we have made several key discoveries about how mutant ASXL1 causes disease. We found that the mutant protein is abnormally stable and accumulates to high levels in cells. This mutant protein disrupts the normal reading of genes by the cell machinery, preventing normal bone marrow cell development. Mutant ASXL1 recruits two other proteins to genes: MECOM and BRD4. Blocking the recruitment of either protein prevents mutant ASXL1 from causing abnormal bone marrow cell growth. However, BRD4 and MECOM normally have opposite effects on gene expression, and it is not clear how both can contribute to the same mutant ASXL1-driven effects. In this proposal, we will perform experiments to understand how ASXL1 is normally broken down, and identify how mutant ASXL1 changes the reading of key genes in bone marrow cells. These studies will allow us to begin developing new drugs for ASXL1-mutant MDS.