Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL.
Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL.
复制标题
作者：
急性淋巴细胞性白血病(ALL)是一种侵袭性血液肿瘤，由淋巴祖细胞恶性转化所致。尽管进行了密集化疗，但20%的儿童和超过50%的成人ALL患者在强化化疗后未能完全缓解或复发，使疾病复发和对治疗的抵抗成为该病治疗的最大挑战。利用全外显子测序，我们在分析的20/103(19%)复发T-ALL和1/35(3%)复发B-前体ALL中鉴定了胞浆5‘-核苷酸酶II基因(NT5C2)的突变，NT5C2编码一种核苷类似物化疗药物失活的5’-核苷酸酶。NT5C2突变蛋白在体外表现出更高的核苷酸酶活性，当在所有淋巴母细胞中表达时，对6-巯基嘌呤和6-硫鸟嘌呤的化疗具有抵抗力。这些结果支持在ALL中激活NT5C2突变和增加核苷类似物代谢在疾病进展和化疗耐药中的突出作用。
Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric and over 50% of adult ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most significant challenge in the treatment of this disease. Using whole exome sequencing, here we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme responsible for inactivation of nucleoside analog chemotherapy drugs, in 20/103 (19%) relapse T-ALLs and in 1/35 (3%) relapse B-precursor ALLs analyzed. 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.
登录
查看更多内容
影响因子：
45.3
作者：
Hof, Jana;Krentz, Stefanie;Kirschner-Schwabe, Renate
通讯作者：
Kirschner-Schwabe, Renate
影响因子：
45.3
作者：
Tallen, Gesche;Ratei, Richard;von Stackelberg, Arend
通讯作者：
von Stackelberg, Arend
影响因子：
4.8
作者：
Jalota, A;Singh, K;Chattopadhyay, S
通讯作者：
Chattopadhyay, S
影响因子：
45.3
作者：
Berg, SL;Blaney, SM;Harris, MB
通讯作者：
Harris, MB
影响因子：
5
作者：
Brouwer, C;Vogels-Mentink, TM;De Abreu, RA
通讯作者：
De Abreu, RA