Nat Med:研究发现急性淋巴细胞性白血病复发机制

科学家日前发现了急性淋巴细胞性白血病（ALL）复发以及产生化疗抗性的酶作用机制，研究报告发表在《自然—医学》杂志上。

ALL的标准治疗方法通常是利用核甘酸类似物破坏DNA合成，从而导致DNA损伤以及肿瘤细胞凋亡。虽然90%的患者经过治疗后有了初步恢复，但仍有相当一部分患者的病情会复发并对治疗药物产生抗性。

Adolfo Ferrando等人利用最新测序技术对产生抗药性患者的编码DNA进行检测，发现ALL细胞中的细胞内5’-核苷酸酶II（NT5C2）基因存在突变。该基因负责编码与核苷酸及核苷酸类似药物的代谢有关的酶。这种突变的酶具有更强的让化疗失效的能力，从而让ALL细胞在一般情况下可以重启核苷酸代谢以抵抗化疗。

由于另一类核苷酸类似物仍然对突变NT5C2的活性具有抵抗性，因此增加该类核苷酸类似物在治疗中的分量或可阻止携带该突变的患者病情复发。

doi:10.1038/nm.3078 
PMC:
PMID:

Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Gannie Tzoneva, Arianne Perez-Garcia, Zachary Carpenter, Hossein Khiabanian, Valeria Tosello, Maddalena Allegretta, Elisabeth Paietta, Janis Racevskis, Jacob M Rowe, Martin S Tallman, Maddalena Paganin, Giuseppe Basso, Jana Hof, Renate Kirschner-Schwabe, Teresa Palomero, Raul Rabadan & Adolfo Ferrando

Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric 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 the most substantial challenge in the treatment of this disease1, 2. Using whole-exome sequencing, we identify mutations in the cytosolic 5′-nucleotidase II gene (NT5C2), which encodes a 5′-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show 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.