Research press release


Nature Medicine

Understanding treatment resistance-causing mutations in leukemias



Adolfo Ferrandoたちは、化学療法抵抗性の患者から得たDNAコード配列を最新のシークエンシング技術を利用して調べ、ALL細胞の細胞質5′-ヌクレオチダーゼII(NT5C2)遺伝子に新たに変異が生じているのを突き止めた。この遺伝子は、ヌクレオシドやヌクレオシド類似体薬の代謝にかかわる酵素をコードしている。その結果生じた変異酵素はこれらの化学療法薬を不活性化する能力が上昇していることから、ALL細胞は化学療法に対抗して自身のヌクレオシド代謝系をつくり直せることが判明した。


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.

doi: 10.1038/nm.3078


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