Defining the Genetic Evolution of Clonal Cytopenias of Undetermined Significance

Myelodysplastic syndromes (MDS) are common blood cancers caused by gene mutations in bone marrow cells. On average, patients with MDS live about 5 years. This is partly because the only therapy that can cure MDS is a bone marrow transplant, and most patients are not eligible because of their advanced age or other illnesses. We want to find ways to prevent MDS before it happens. MDS often happens after a condition called clonal cytopenia of undetermined significance (CCUS), a disease also caused by DNA mutations. Recent data suggest that for some patients, CCUS is just as severe as MDS, yet there is still no approved treatment for CCUS. Understanding why some CCUS patients’ disease progresses and others do not is important if we want to try to prevent MDS. We think that CCUS progression happens when cells gain new mutations or when cells with certain mutations grow more than others. We aim to find out how cells change over time in CCUS and MDS, in order to identify treatments that can prevent or delay disease progression. To understand why some patients have worsening disease and some do not, we will identify the mutations in their blood cells. We will use whole genome sequencing (WGS) of DNA to find all the mutations in the blood cells of patients with CCUS and very low-risk MDS. We will use these mutations to learn how their cancer changes over time so we can predict who might benefit from early treatment before disease progression occurs. We will identify mutations in multiple blood samples collected over time from 102 CCUS and MDS patients, some who experienced disease progression and others who did not. We will test whether we can detect the growth of mutated cells before a patient develops symptoms or experiences disease progression. This could tell us when to start therapy that may prevent disease progression. Then we will study these mutations in blood cells in the lab to learn how they change the way blood cells grow. We hope to learn more about why some mutations occur before others in the same patient, and uncover new ways to kill blood cancer cells based on their mutations. Finally, we believe we will learn how to identify CCUS patients who could be included in MDS clinical trials.