Pharmacogenomics of Thiopurine Therapy in Hematological Disorders

Thiopurines such as azathioprine and 6-mercaptopurine remain cornerstones of maintenance regimens in acute lymphoblastic leukaemia and other haematological conditions. Their therapeutic effect depends on intracellular conversion to thioguanine nucleotides, which incorporate into DNA and disrupt proliferative capacity. However, narrow therapeutic indices and unpredictable toxicity profiles have historically limited their safe use. Pharmacogenomic profiling of enzymes that activate, inactivate or sanitise nucleotide pools—most notably thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15)—has enabled pre-emptive dose individualisation to mitigate myelosuppression and hepatotoxicity. Emerging evidence also implicates other targets, including inosine triphosphate pyrophosphatase (ITPA) and auxiliary methyltransferases, in modulating metabolite levels. Integration of genetic screening with therapeutic drug monitoring, such as measuring DNA-bound thioguanine and enzyme activity assays, has refined risk stratification, informed dynamic dose adjustment and enhanced long-term outcomes. Continued research is extending this precision-medicine framework across diverse ethnic groups and identifying novel loci that contribute to inter-individual variability in treatment response and adverse events.

Research from Nature Portfolio

Recent structural biology studies have resolved high-resolution crystal structures of key nucleotide-sanitising enzymes, revealing how discrete active-site residues govern substrate selectivity and influence the stability of thioguanine metabolites. These insights clarify the mechanistic basis by which common polymorphic variants impair enzymatic function, precipitating accumulation of cytotoxic nucleotides and heightened myelotoxicity. Concurrently, comprehensive genomic analyses using next-generation sequencing in cohorts treated with thiopurines have uncovered rare and novel TPMT alleles that escape detection by routine assays yet correlate strongly with reduced enzyme activity and clinical toxicity. A gene-based association framework further identified auxiliary loci that modulate thiopurine clearance, underscoring the multilocus architecture of drug response and paving the way for expanded pharmacogenomic panels.

Pharmacogenomics of Thiopurine Therapy in Hematological Disorders publication trend

The graph below shows the total number of articles in pharmacogenomics of thiopurine therapy in hematological disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Thiopurines: A class of purine analogue drugs, including azathioprine and 6-mercaptopurine, used to suppress cell proliferation.

Pharmacogenomics: The study of how genetic variation influences individual responses to drugs, guiding personalised therapy.

Thioguanine nucleotides (TGNs): Active metabolites of thiopurines that incorporate into DNA and RNA, mediating cytotoxic effects.

Thiopurine S-methyltransferase (TPMT): An enzyme that methylates and inactivates thiopurine metabolites; genetic variants can reduce its activity.

Nudix hydrolase 15 (NUDT15): An enzyme that dephosphorylates thioguanine nucleotides; loss-of-function variants increase toxicity risk.

Inosine triphosphate pyrophosphatase (ITPA): An enzyme that hydrolyses noncanonical nucleotides; polymorphisms can alter thiopurine metabolite balance.

References

1. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nature Communications (2015).
2. The Promise of Pharmacogenomics in Reducing Toxicity during Acute Lymphoblastic Leukemia Maintenance Treatment. Genomics Proteomics & Bioinformatics (2017).
3. Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations. Leukemia (2022).
4. Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?. BMC Cancer (2018).
5. ITPA, TPMT, and NUDT15 Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia. Frontiers in Pharmacology (2019).
6. Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort. Scientific Reports (2016).
7. Cloning, Expression, and Characterization of a Human Inosine Triphosphate Pyrophosphatase Encoded by the ITPAGene*. Journal of Biological Chemistry (2001).