Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5′-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.

中文翻译：

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NT5C2突变复发性急性淋巴细胞白血病的克隆进化机制

复发性急性淋巴细胞白血病 (ALL) 与化疗耐药和预后不良有关。5'-核苷酸酶、胞质 II (NT5C2) 基因的功能获得性突变诱导对 6-巯基嘌呤的抗性，并选择性地存在于复发性 ALL 中。然而，在白血病开始、疾病进展和复发期间，NT5C2 突变驱动的克隆进化所涉及的机制仍然未知。在这里，我们使用条件诱导型白血病模型来证明 NT5C2(R367Q) 的表达，一种非常普遍的复发性 ALL NT5C2 突变，以白血病细胞生长受损和白血病起始为代价诱导对 6-巯基嘌呤化疗的耐药性细胞活性。NT5C2+/R367Q 突变细胞的适应性丧失表型与嘌呤向细胞外空间的过量输出和细胞内嘌呤-核苷酸库的耗竭有关。因此，通过抑制肌苷 5'-单磷酸脱氢酶 (IMPDH) 来阻断鸟苷合成可诱导对 NT5C2 突变白血病淋巴母细胞的细胞毒性增加。这些结果将 NT5C2 突变的适应性成本和化疗耐药性确定为形成复发 ALL 克隆进化的关键进化驱动因素，并支持 IMPDH 抑制在 ALL 治疗中的作用。