Recent Scientific Findings
The CPPT has brought national and international recognition to Pediatrics research and education programs of the University of Tennessee Health Science Center. The CPPT faculty have established a major new initiative in pharmacogenomics, the genetic basis for inter-individual differences in drug disposition and drug effects. The potential power of this work is illustrated by research of CPPT faculty on the genetic polymorphism of thiopurine methyltransferase (TPMT), a drug metabolizing enzyme that exhibits marked differences in activity among children, based on inheritance from their parents.
During the past five years, our research has focused on elucidating the genetic determinants of inter-individual differences in the metabolism and effect of thiopurine medications, focusing primarily on the widely prescribed antileukemic agent mercaptopurine. Accomplishments include identifying the genetic basis for inherited differences in thiopurine S-methyltransferase (TPMT) (Krynetski et al, Proc Natl Acad Sci USA, 1995; Tai et al, Am J Hum Gen, 1996), defining the molecular mechanisms involved in loss of TPMT activity with the alleles (Tai et al, Proc Natl Acad Sci USA, 1997), developing molecular diagnostics to identify individuals with this inherited trait (Yates et al, Ann Intern Med, 1997), cloning and characterizing the human TPMT promoter region (Fessing et al, J Biochem, 1998), isolating the mouse TPMT gene (Fessing et al, FEBS Lett, 1998), defining ethnic differences in the TPMT polymorphism in African-Americans and Caucasians (Hom et al, Hum Mol Genet, 1999) and elucidating of the clinical importance of the TPMT polymorphism in determining the pharmacological effects of mercaptopurine (Relling et al, J Natl Cancer Inst, 1999; Relling et al, Lancet, 1999). Although the greatest risk of toxicity is in patients who inherit complete TPMT deficiency, we have recently established that patients with heterozygous phenotypes (~10% of patients) are at intermediate risk of thiopurine toxicity (Relling et al, J Natl Cancer Inst, 1999). Hence, TPMT gentotype is an important determinant of thipourine toxicity in a substantial proportion of patients. These studies are described in greater detail in the publications listed in the 5 year Self-Study appendices, and concise summaries can be found in several invited reviews published during the past 5 years (Krynetski and Evans, Am J Hum Genet, 1998; Evans and Relling, Science, 1999; McLeod et al, Leukemia, 2000). Our ongoing studies are designed to elucidate additional molecular mechanisms that determine TPMT activity, including potential polymorphisms in the TPMT promoter that may underlie the 4-fold range of TPMT activity amongst patients who have a wild type TPMT coding region. We are also creating a TPMT knockout mouse model that will be used to further elucidate the role of this polymorphism in determining thiopurine efficacy and toxicity.
Based on the work, TPMT deficiency can now be diagnosed using genomic DNA to detect the signature mutations in TPMT mutant alleles discovered at St. Jude. These molecular diagnostic test are now available to pediatric hematologists-oncologists and other clinicians using thiopurine medications for the treatment of leukemia and non-malignant diseases (rheumatoid arthritis, inflammatory bowel disease, immuno-suppressants for solid organ transplantation). To make TPMT genotyping widely available to clinicians, St. Jude licensed their diagnostic tests to PPGx, Inc., which now offers CLIA-approved TPMT genotyping in the U.S. (Research Triangle Park, NC) and Europe (Cambridge, UK).