Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.67 (thiopurine methyltransferase)
 551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The current cure rate of 80% in childhood acute lymphoblastic leukemia (ALL) attests to the effectiveness of risk-directed therapy developed through well-designed clinical trials. The ongoing Total Therapy Study XV at St. Jude Children's Research Hospital was designed to further increase cure rate and to improve quality of life. The study consists of intensive systemic and intrathecal therapy but does not include cranial irradiation, irrespective of a patient's risk features. The intensity of postremission consolidation, continuation and reinduction therapy is based on the level of minimal residual disease at the end of induction, as measured by both flow cytometric detection of aberrant immunophenotypes and polymerase-chain-reaction amplification of clonal antigen-receptor gene rearrangements. Status of thiopurine methyltransferase is determined prospectively for treatment modification. Pharmacogenetic, pharmacodynamic, gene expression and proteomic profiling studies of host normal cells and leukemic cells are performed in parallel to elucidate the mechanisms of drug resistance and to advance our understanding of leukemogenesis.
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PMID:Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia. 1512 3

Immunosuppressive thiopurines like azathioprine, 6-mercaptopurine, and thioguanine are commonly used in inflammatory and neoplastic disorders. A subset of these patients are genetically slow metabolizers due to point-mutations in enzyme thiopurine S-methyltransferase (TPMT), and are at a higher risk of hematologic toxicity and leukemogenesis. We present such a patient who was a slow metabolizer for azathioprine, and developed a rapidly lethal form acute myeloid leukemia after relatively low dose exposure to the drug. There was prominent hemophagocytic activity in the bone marrow, and cytogenetic analysis showed a complex karyotype with monosomy 7, but no involvement of chromosome 8.
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PMID:Azathioprine-associated acute myeloid leukemia in a patient with Crohn's disease and thiopurine S-methyltransferase deficiency. 1769 2

Although somatically acquired genomic alterations have long been recognized as the hallmarks of acute lymphoblastic leukemia (ALL), the last decade has shown that inherited genetic variations (germline) are important determinants of interpatient variability in ALL susceptibility, drug response, and toxicities of ALL therapy. In particular, unbiased genome-wide association studies have identified germline variants strongly associated with the predisposition to ALL in children, providing novel insight into the mechanisms of leukemogenesis and evidence for complex interactions between inherited and acquired genetic variations in ALL. Similar genome-wide approaches have also discovered novel germline genetic risk factors that independently influence ALL prognosis and those that strongly modify host susceptibility to adverse effects of antileukemic agents (eg, vincristine, asparaginase, glucocorticoids). There are examples of germline genomic associations that warrant routine clinical use in the treatment of childhood ALL (eg, TPMT and mercaptopurine dosing), but most have not reached this level of actionability. Future studies are needed to integrate both somatic and germline variants to predict risk of relapse and host toxicities, with the eventual goal of implementing genetics-driven precision-medicine approaches in ALL treatment.
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PMID:Inherited genetic variation in childhood acute lymphoblastic leukemia. 2599 54