PROJECT SUMMARY

MDS is fundamentally a competition disease, where mutant cells win over normal cells, and take over the normal production of blood. Clonal competition is a normal process in the blood, where our stem cells are constantly competing with each other for the signals that allow them to proliferate within the bone marrow. However, MDS cells cheat their way into this competition, dramatically affecting the fitness of normal cells. We know that most of the mutations present in MDS cells accumulate with age without causing any symptoms, and then something triggers them to stop making normal blood cells. Our hypothesis is that we can prevent MDS progression if we find ways to make our healthy stem cells stronger, or ways to reduce the fitness of MDS cells. To find these mechanisms we have to look early on at the arms race between the mutant and normal cells, and then find what are the machineries that MDS mutations have that distinguish them from normal cells. For this we will a state-of-the-art genetic tool that simultaneously allows us to find these machineries and assess the fitness of each mutant cell, from thousands of different cells at the same time. We hope that elucidating the arms race between MDS and normal cells will rapidly lead to novel treatments and innovative approaches for MDS patients.