Mechanisms of CNOT3 Tumor Suppression in T-ALL and Identification of New Drugs That Specifically Kill CNOT3-Deficient T-ALL Cells

Background

Acute Lymphoblastic Leukemia (ALL) is the most common leukemia among children making up 80% of all childhood leukemia cases. Among acute leukemia, T-cell acute lymphoblastic leukemia (T-ALL), which accounts for about 15% of pediatric cases, is aggressive hematologic tumors arising from progenitor cells that meant to become T cells. Understanding the biology of T-ALL may identify new targets for T-ALL therapy and open the way for the development of new drugs. Very recently, scientists identified a new class of recurrent somatic mutations affecting a gene called CNOT3 in T-ALL patient samples. This finding suggested that loss of CNOT3 function contributes to the pathogenesis of T-ALL in humans. However, virtually nothing is known about the role of CNOT3 in T-ALL pathogenesis.

Project Goal

In this project, I plan to study how loss of CNOT3 leads to the development of T-ALL using human T-ALL cells, zebrafish T-ALL models and mouse models. Furthermore, I will conduct screens to search for new drugs that can specifically kill CNOT3 deficient T-ALL cells, but do not harm normal cells in the T-ALL patients. Dr. Thomas Look's laboratory at Dana-Farber Cancer Institute has pioneered the use of multiple models to study childhood T-ALL. I believe that my proposed study in Dr. Look's laboratory will profoundly expand our knowledge about CNOT3 deficient T-ALL and identify new drugs for T-ALL therapy as a final goal.