Modeling relapsed hypodiploid B-cell acute lymphoblastic leukemia using humanized in vivo systems
Dr. Matthew Witkowski – University of Colorado Denver, AMC and DC
Acute Lymphoblastic Leukemia (B-ALL) is the most common childhood cancer and results from excessive numbers of immature white blood cells, known as B-cell progenitors, overwhelming normal bone marrow and major organ function. One intriguing form of leukemia is known as “hypodiploid” ALL - “hypo” meaning less than normal, and “diploid” referring to the two sets of chromosomes inherited from either parent. Hypodiploid leukemia is frequently resistant to chemotherapy leading to a fatal disease relapse. Multiple studies have identified specific gene mutations and chromosome losses present in hypodiploid leukemia cells, yet there are no experimental systems to test treatment alternatives. We aim to generate experimental platforms mimicking how hypodiploid ALL cells emerge and fail to respond to therapy. To achieve this, we will analyze bone marrow samples from hypodiploid ALL patients at disease diagnosis and disease relapse to determine leukemic cells change their gene expression to adapt and resist therapy in patients. Mouse models have proven to be an invaluable tool for exploring new treatment options for B-ALL. We will use genome engineering tool, CRISPR, to mutate genes believed to cause hypodiploid ALL formation in order to determine which genetic mutations transform a healthy human B-cell progenitor into deadly hypodiploid ALL cell. We believe that setting up these tools will enable future experiments testing new therapeutic strategies aimed at preventing deadly relapse.
