An enzyme-based mechanism is outlined in Nature Medicine explaining how acute lymphoblastic leukaemias (ALLs) relapse and develop resistance to chemotherapy.

The standard therapy for ALL is treatment with nucleoside analogs which disrupt DNA synthesis, causing DNA lesions and tumour cell death.

But despite intensive chemotherapy, 20% of paediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy one of the biggest challenges faced in treatment of this disease.

The specific mechanisms mediating escape from therapy, disease progression and leukaemia relapse remain largely unknown.

In the current study. Adolfo Ferrando and colleagues from the Institute for Cancer Genetics, Columbia University, New York, USA, performed whole-exome sequencing of matched DNA samples taken from chemotherapy resistant patients at diagnosis, remission and relapse.

The investigators identified mutations in the cytosolic 5′-nucleotidase II gene (NT5C2), which encodes a 5′-nucleotidase enzyme responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapsed T cell ALLs and 1/35 (3%) relapsed B-precursor ALLs.

Furthermore, NT5C2 mutant proteins showed increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. “These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL,” write the authors.

Since another class of nucleoside analogs remains resistant to the activity of mutant NT5C2, the authors suggest that increasing its incorporation into treatment regimens could help prevent relapse of patients with these mutations.

Reference

G Tzoneva, A Perez-Garcia, Z Carpenter, et al.Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nature Medicine. doi:10.1038/nm.3078