Tpmt Gene Expression is Increased During Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia Patients in a TPMT Gene Promoter Variable Number of Tandem Repeat-Dependent Manner

Abstract

The TPMT promoter genetic variants need to be considered at the very beginning of the maintenance therapy for childhood ALL patients. The TPMT promoter VNTR region may serve as a pharmacogenomic biomarker when introducing thiopurine therapy.

The Promise of Pharmacogenomics in Reducing Toxicity during Acute Lymphoblastic Leukemia Maintenance Treatment

“…As a result of trustworthy sources becoming more numerous, clinical actions are being shaped. Hospitals, such as St. Jude Children's Research Hospital, have already begun addressing the problem of prescribing the necessary dosage, while simultaneously avoiding unneeded toxicities by genotyping patients that are prescribed 6-MP, specifically looking for TPMT variants [16]. However, other hospitals primarily genotype for TPMT following the onset of symptoms of myelosuppression and clinical practices surrounding treatment with MTX that incorporate pharmacogenomics have not yet been developed.…”

“…These variant alleles lead to decreased activity of TPMT , and result in a higher risk of toxicity. TPMT expression may also be influenced by environmental factors, as evidenced by the increased expression during thiopurine treatment and decreased expression with age and renal malfunction [16]. In addition, variants in linkage disequilibrium with the most common TPMT single nucleotide polymorphism (SNP), 719A>G (rs1142345), have also been connected to altered TPMT expression [16].…”

“…TPMT expression may also be influenced by environmental factors, as evidenced by the increased expression during thiopurine treatment and decreased expression with age and renal malfunction [16]. In addition, variants in linkage disequilibrium with the most common TPMT single nucleotide polymorphism (SNP), 719A>G (rs1142345), have also been connected to altered TPMT expression [16]. Genome-wide association study (GWAS) analysis demonstrates that TPMT polymorphisms *3A and *3C have the strongest associations with toxicity.…”

Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: influence on treatment response

“…It is coded by the TPMT gene and exerts its effect via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a by-product 1–3. Thiopurine drugs, mainly 6-mercaptopurine (6-MP), and its prodrug azathioprine (AZA), are implicated as anti-metabolite cytotoxic and immunosuppressive agents in the treatment of malignancies such as acute lymphoblastic leukemia (ALL), inflammatory disorders like inflammatory bowel disease (IBD) and many autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), autoimmune hepatitis (AIH) and generalized eczematous disorders 3–5.…”

“…It is coded by the TPMT gene and exerts its effect via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a by-product 1–3. Thiopurine drugs, mainly 6-mercaptopurine (6-MP), and its prodrug azathioprine (AZA), are implicated as anti-metabolite cytotoxic and immunosuppressive agents in the treatment of malignancies such as acute lymphoblastic leukemia (ALL), inflammatory disorders like inflammatory bowel disease (IBD) and many autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), autoimmune hepatitis (AIH) and generalized eczematous disorders 3–5. However, gastrointestinal disturbances (like nausea and vomiting), rashes, as well as more serious adverse drug reactions (ADRs) like bone marrow toxicity, hepatotoxicity and pancreatitis can lead to discontinuation of therapy in up to one-third of patients;6 these factors limit the use of these drugs 2…”