Yang Lab

Although the cure rate of pediatric leukemia is high, this was achieved by brute-force approach using cytotoxic chemotherapy for decades. We are leading efforts at St. Jude to develop the next generation of leukemia therapy with surgical precision, leveraging genetic insights developed over the past 10 years. Studying 1000+ leukemia patients across the US, we are examining their pharmacotype and profiling genomes at the same time. Our aim is to construct a gene-drug connectivity map to identify biomarkers and predictors of patients’ response to novel leukemia drugs. We have already started developing a biomarker-informed clinical trial for pediatric T-ALL based on this work and look forward to applying this approach to other subtypes of ALL. 

The drugs currently used to treat pediatric leukemia are highly efficacious, but with profound adverse effects. It is important that we understand the underlying causes of toxicity and try to mitigate this deleterious response in patients. Again, our team takes a genomic approach – comparing patients with vs without toxicity in genome-wide scans to identify specific variants associated with the side effects. Our group discovered genetic polymorphism in the NUDT15 gene that puts children at a dramatic risk of myelosuppression following treatment of an anti-leukemia drug called thiopurine. By elucidating the molecular mechanism of how NUDT15 modulates thiopurine metabolism, we developed ways to use pharmacogenomics to individualize their therapy, reducing associated toxicities by almost 90%. This work has led to the change of thiopurine drug label by the Food and Drug Administration. We are currently exploring pharmacogenomics of other pediatric cancer drugs.

Fundamental to our work is the understanding that children are at varied risk for developing leukemia. We use genome wide studies to explore the genetic variants that drive the formation of leukemia. Our laboratory, in collaboration with other investigators at, and beyond, St. Jude, has developed cohorts of children with leukemia, and their healthy counterparts. We compare the genetic makeups of each population and identify putative risk factors – genes enriched in afflicted children. Additionally, we work to identify rare families with multiple cases of leukemia, suggesting highly penetrant genetic risk factors. We utilize engineered mouse models to manipulate genes of interest identified in these studies and investigate the resulting hematopoietic phenotypes. Ultimately, our goal is to understand the genetic basis for susceptibility to pediatric leukemia.