PROJECT SUMMARY

Aging can be associated with alterations in the production of the different cells that compose the blood. These changes can manifest as anemia, due to a decreased number of red cells; leukopenia, related to a decrease in white blood cells; and thrombocytopenia, due to a decreased number of platelets. Clinically, these blood deficiencies translate into symptoms of fatigue, increased risk of infections, and bleeding. As we age, the bone marrow stem cells that give rise to all the different cells in the blood can acquire genetic mutations. Initially, these mutations can start by affecting only small populations of marrow cells, a process known as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS). Over time, and under pressure from other factors, such as inflammation or chemotherapy used to treat other cancers, these CHIP/CCUS clones can expand and develop into a type of leukemia, known as myelodysplastic syndrome (MDS). We search to understand how CHIP progresses to MDS with the main goal of developing clinical strategies to stop this process. In previous work in Dr. Colla’s laboratory, we found that these mutant cells in the bone marrow produce very high levels of a protein known as interleukin 1β (IL1β). We believe that this protein can provide an advantage to the mutant cells and kill the normal ones. Based on these results, we have started dissecting the effects of an inhibitor of IL1β, known as canakinumab, on bone marrow function. In the first year of this proposal, we studied the cellular and molecular effects of canakinumab in bone marrow cells of patients with low-risk MDS enrolled in a clinical trial of canakinumab. The results of our studies have allowed us to open a new clinical trial to treat patients with early-stage disease as CCUS.