Oncometabolite-induced DNA replication defects in leukemia
Unlike normal blood cells which divide only when necessary, leukemic cells divide uncontrollably and in doing so are constantly duplicating their genetic material (i.e., their DNA) in a process called “DNA replication”. Chemotherapy drugs cause lethal damage specifically to replicating DNA in cancer cells, but spare normal cells which rarely undergo DNA replication. This explains in large part how such drugs can preferentially kill cancer cells over normal cells. Our laboratory studies biochemical mechanisms that protect cancer cells against DNA damage caused by chemotherapy drugs, thereby decreasing the efficacy of cancer-killing treatments. To fit in the tiny confines of the cells, DNA is wrapped around molecules called “histones” that strongly influence how cancer cells respond to DNA damage caused by chemotherapy. We also know that leukemia cells produce abnormal chemicals that modify the function of histones in unwanted ways. We propose to directly evaluate the impact of these chemicals on the ability of cancer cells to respond to chemotherapy. We expect that our research will lead to new, more efficient and personalized strategies to treat leukemia.