Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.

中文翻译：

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IDH2抑制剂enasidenib治疗急性髓细胞白血病的克隆异质性。

编码异柠檬酸脱氢酶 2 (IDH2) 的基因突变发生在几种类型的癌症中，包括急性髓性白血病 (AML)。在模型系统中，突变 IDH2 导致造血分化停滞。Enasidenib 是一种突变 IDH2 的选择性小分子抑制剂，通过促进白血病细胞分化，在 40% 的复发/难治性 AML 患者中产生临床反应。在这里，我们研究了对依那西尼治疗的反应和获得​​性耐药的克隆基础。使用连续的患者样本，我们确定了不同分化阶段的造血细胞群的克隆结构。治疗前，IDH2 突变克隆表现出不同的分化停滞。Enasidenib 治疗促进了终末或祖先突变克隆的造血分化；不太频繁，处理促进了非突变细胞的分化。配对诊断/复发样本的分析未发现复发时 IDH2 的第二位点突变。相反，复发是由克隆进化或终端或祖先克隆的选择引起的，因此突出了多种旁路​​途径，这些途径可能有可能成为恢复分化停滞的目标。这些结果显示了在不同分化阶段的细胞群中克隆结构的映射如何揭示治疗反应和复发期间克隆的反应和进化。从而突出了可能针对恢复分化停滞的多种旁路途径。这些结果显示了在不同分化阶段的细胞群中克隆结构的映射如何揭示治疗反应和复发期间克隆的反应和进化。从而突出了可能针对恢复分化停滞的多种旁路途径。这些结果显示了在不同分化阶段的细胞群中克隆结构的映射如何揭示治疗反应和复发期间克隆的反应和进化。