Grants - V Scholar Grants - Massachusetts - 2019

Zuzana Tothova, M.D., Ph.D.

Abeloff V Scholar* (Tied for Top Rank)

Funded by the Constellation Gold Network Distributors

Use of a new DNA sequencing technology called next generation sequencing (NGS) has significantly improved our ability to describe the genetic basis of human cancers, including blood cancers like leukemia. However, we do not fully understand how most of the genes that cause leukemia play a role in this disease and how to target them with therapy. We know that mutations in a protein complex called the cohesin complex, which normally helps genes turn on and off, frequently occur in patients with blood cancers. These mutations usually occur during the process of disease progression from pre-cancerous states to highly aggressive cancer types. Cohesin mutations are found in 10-20% of patients with blood cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) and are associated with poor survival. With this grant, we will focus on exploring how DNA changes mediated by the cohesin complex play a role in disease progression. Specifically, we will examine folding of DNA into loops and organization of chromatin during the steps of disease progression. Treatment options for patients with blood cancers are limited, and by expanding our understanding of the mechanisms by which leukemia causing genes contribute to disease development, we aim to inform the design of urgently needed therapies for patients. The impact of this work is far reaching and may extend to patients with other blood cancers, including chronic myelomonocytic leukemia (CMML) and chronic myeloid leukemia (CML), as well as patients with bladder cancer, glioblastoma, Ewing sarcoma and breast cancer.