Function of IKZF1 in DNA Damage Responses in Normal and Malignant Pre-B Cells

Background:
Leukemia is the most common pediatric malignancy and advances in treatment have resulted in remarkable improvements in survival.  However, patients with high-risk disease still have a poor prognosis despite intensive treatment regimens.  Recently, mutations in the transcription factor IKZF1 (Ikaros) have been identified in high-risk pediatric leukemia. IKZF1 regulates expression of a numerous genes involved in various aspects of normal B cell maturation. Mutations in IKZF1 alter B cell development and establish a cellular program that supports generation of leukemias. Patients with IKZF1 mutations are classified as high-risk due to historically poor responses to current treatment.  While recent work has elucidated how IKZF1 alterations lead to leukemic development, we do not understand how changes in IKZF1 affect responses to chemotherapy. The goal of this project is to characterize how alterations in IKZF1 affect cellular responses to chemotherapy. Preliminary work has demonstrated that IKZF1 controls expression of genes involved in DNA repair pathways.

Project Goal:

We hypothesize that mutation of IKZF1 impairs the ability of cells to appropriately respond to DNA damage. Decreased DNA damage responses would permit cells to tolerate DNA injury and not trigger appropriate cell death mechanisms. Additionally, reduction in DNA repair mechanisms could lead to increased genomic instability and risk of translocations or other mutations that would further support survival of leukemic cells. Experiments will investigate how mutations in IKZF1 impact cellular responses to DNA damage encountered during normal development and after exposure to chemotherapeutic agents. Understanding these processes will provide insights into the development and treatment of leukemia.