Acute lymphocytic leukemia (ALL) is the most common type of childhood cancer. It is important to understand the genomics of ALL so that more effective therapies can be developed.
The Therapeutically Applicable Research to Generate Effective Therapies (TARGET) high-risk ALL initiative is a collaborative, international project sponsored by the National Cancer Institute. The goal of this initiative is to understand the genetic processes that cause ALL to develop.
Stephen P. Hunger, MD, and researchers at the Center for Childhood Cancer Research are leading the efforts in TARGET to identify the specific genes responsible for the development of high-risk subsets of ALL, with a focus on identifying potential new therapeutic targets.
In the first phases of this project, investigators focused on a subgroup of pediatric ALL patients who were at high risk for treatment failure. Targeted sequencing was performed on approximately 125 genes in several hundred patients characterized as high risk at diagnosis based on clinical characteristics. Researchers wanted to see what the genetic correlates were to clinical characteristics.
In the first phase, the genes chosen for targeted sequencing were genes that were either known to be involved with leukemia or other subtypes of cancer. In the second phase, comprehensive sequencing of several hundred cases was performed, including sequencing DNA from normal cells (germline) and leukemia cells obtained at the time of initial diagnosis and relapse. Several different sequencing technologies were used: whole exome sequencing, whole genome sequencing, and RNA sequencing or transcriptomic sequencing.
This combination of sequencing technologies has successfully identified abnormalities that occur consistently in different patients, and offers a potential target for different therapeutic interventions. One major new subtype discovered is called Philadelphia chromosome-like (Ph-like ALL), and several new precision medicine clinical trials are being developed for this subtype.