Cooperative mutagenesis driving pediatric pre-B cell leukemia

Dr. Abby Green, M.D. – Washington University, School of Medicine, St. Louis, MO

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. ALL, like most cancers, develops because of damage to DNA, the blueprints of every human cell. Many causes of DNA damage in adult-onset cancers are known. For example, tobacco, alcohol, and sunlight cause DNA damage that can lead to cancer. Children are not exposed to these DNA-damaging toxins in the same doses or durations as adults, therefore how DNA mistakes are acquired in pediatric cancers is unknown. We are interested in the causes of DNA damage that spur development of pediatric cancer, especially leukemia. We suspect that damage to DNA in children occurs when normal functions of cells become unregulated.

ALL arises from abnormal immune cells, specifically B cells. In normal B cell development, purposeful DNA damage occurs to optimize cell function. We hypothesize that these sources of purposeful DNA damage can go awry. We have generated a unique system to study sources of purposeful DNA damage in B cells in different contexts. We will determine 1) what causes developing B cells to be vulnerable to DNA damage, and 2) how sources of purposeful DNA damage go awry to cause leukemia to develop. We have generated unique systems to study purposeful sources of DNA damage, therefore mimicking the actual genetic events that drive healthy B cells to become cancer. Our long-term goal is to develop strategies to prevent or harness abnormal DNA damage to limit leukemia development and devise new treatments.