Mutations in the isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 genes are frequently observed in a wide variety of hematologic malignancies, including myeloid and T-cell leukemias. In this study, we generated Idh2R140Q transgenic mice to examine the role of the Idh2R140Q mutation in leukemia. No leukemia developed in Idh2R140Q transgenic mice, suggesting a need for additional genetic events for leukemia development. Because myeloid cells from NUP98-HOXD13 fusion ( NHD13 ) transgenic mice frequently acquire somatic Idh mutations when they transform to acute myeloid leukemia, we generated Idh2R140Q/NHD13 double transgenic mice. Idh2R140Q/NHD13 transgenic mice developed an immature T-cell leukemia with an immunophenotype similar to double-negative 1 (DN1) or DN2 thymocytes. Idh2R140Q/NHD13 leukemic cells were enriched for an early thymic precursor transcriptional signature, and the gene expression profile for Idh2R140Q/NHD13 DN1/DN2 T-ALL closely matched that of human early/immature T-cell precursor (EITP) acute lymphoblastic leukemia (ALL). Moreover, recurrent mutations found in patients with EITP ALL, including KRAS, PTPN11, JAK3, SH2B3 , and EZH2 were also found in Idh2R140Q/NHD13 DN1/DN2 T-ALL. In vitro treatment of Idh2R140Q/NHD13 thymocytes with enasidenib, a selective inhibitor of mutant IDH2, led to a marked decrease in leukemic cell proliferation. These findings demonstrate that Idh2R140Q/NHD13 mice can serve as a useful in vivo model for the study of early/immature thymocyte precursor acute lymphoblastic leukemia development and therapy. Significance: T-cell leukemia induced in Idh2R140Q/NUP98-HOXD13 mice is immunophenotypically, transcriptionally, and genetically similar to human EITP ALL, providing a model for studying disease development and treatment.

中文翻译：

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突变体 Idh2 与 NUP98-HOXD13 融合诱导早期未成熟胸腺细胞前体 ALL

异柠檬酸脱氢酶 1 ( IDH1 ) 和 IDH2 基因的突变经常在多种血液恶性肿瘤中观察到，包括骨髓和 T 细胞白血病。在这项研究中，我们生成了 Idh2R140Q 转基因小鼠来检查 Idh2R140Q 突变在白血病中的作用。在 Idh2R140Q 转基因小鼠中没有出现白血病，这表明白血病发展需要额外的遗传事件。由于来自 NUP98-HOXD13 融合 ( NHD13 ) 转基因小鼠的骨髓细胞在转化为急性髓细胞白血病时经常获得体细胞 Idh 突变，因此我们生成了 Idh2R140Q/NHD13 双转基因小鼠。Idh2R140Q/NHD13 转基因小鼠发展为未成熟 T 细胞白血病，其免疫表型类似于双阴性 1 (DN1) 或 DN2 胸腺细胞。Idh2R140Q/NHD13 白血病细胞富含早期胸腺前体转录特征，Idh2R140Q/NHD13 DN1/DN2 T-ALL 的基因表达谱与人类早期/未成熟 T 细胞前体 (EITP) 急性淋巴细胞白血病 (ALL ）。此外，在 EITP ALL 患者中发现的复发性突变，包括 KRAS、PTPN11、JAK3、SH2B3 和 EZH2，也在 Idh2R140Q/NHD13 DN1/DN2 T-ALL 中发现。Idh2R140Q/NHD13 胸腺细胞用 enasidenib（突变 IDH2 的选择性抑制剂）体外处理导致白血病细胞增殖显着降低。这些发现表明，Idh2R140Q/NHD13 小鼠可作为研究早期/未成熟胸腺细胞前体急性淋巴细胞白血病发展和治疗的有用体内模型。意义：