This project characterises abnormal cell death and gene expression changes in myelodysplasia. The results will allow better understanding of current therapies and open new therapeutic avenues.
Myelodysplasia is a premalignant condition which progresses in many cases to acute myeloid leukemia. In early myelodysplasia, the premalignant cells die (via a process known as programmed cell death) at an increased rate, leading to fewer blood cells in circulation. This causes the symptoms of myelodysplasia, such as fatigue and low immunity.
One of the keys to the progression of the disease is an increased survival of the cells. In late myelodysplasia and acute myeloid leukemia, the cells have developed a means of overcoming this programmed death, allowing them to accumulate.We have an animal model of myelodysplasia which accurately mimics the cell death seen in human myelodysplasia.
We have investigated the molecular events that result in this increase in cell death, and shown that it is possible to prevent the programmed cell death by over-expressing a single gene, BCL2. Over-expressing this gene alleviate the symptoms of early MDS by restoring the number of blood cells in circulation to normal.
Somewhat surprisingly, over-expressing this gene also delays progression of the disease to acute myeloid leukemia.If we can find a way of simulating the over-expression of BCL2 in myelodysplasia patients (by use of a drug that simulates the actions of BCL2, for example), then we may be able to treat myelodysplasia effectively, and eliminate the risk of progression to acute myeloid leukemia.