Understanding treatment resistance-causing mutations in leukemias

An enzyme-based mechanism that explains how acute lymphoblastic leukemias (ALLs) relapse and develop resistance to chemotherapy is reported in a study published online this week in Nature Medicine.

The standard therapy for ALL is treatment with nucleoside analogs which disrupt DNA synthesis, causing DNA lesions and tumor cell death. Although about 90% of patients show an initial remission of the disease, a substantial proportion of them relapse and stop responding to these drugs.

Adolfo Ferrando and colleagues interrogate the coding DNA from chemotherapy-resistant patients using last generation sequencing technology and identify newly arising mutations in the cytosolic 5’-nucleotidase II (NT5C2) gene in ALL cells. This gene encodes an enzyme involved in the metabolism of nucleosides and nucleoside-analog drugs. The resulting mutant enzyme exhibits increased capacity to inactivate these chemotherapeutics, proving that ALL cells can genetically re-wire their nucleotide metabolism to counteract chemotherapy.

As another class of nucleoside analogs remained resistant to the activity of mutant NT5C2, its increased incorporation into treatment regimens could impede the relapse of patients with these mutations.