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首页> 外文期刊>Cellular Physiology and Biochemistry >KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia
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KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia

机译：KRAS（G12D）与AML1 / ETO合作启动模仿人类急性髓样白血病的小鼠模型

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biBackground/Aims /i/bIt has been demonstrated that iKRAS/i mutations represent about 90% of cancer-associated mutations, and that iKRAS/i mutations play an essential role in neoplastic transformation. Cancer-associated RAS mutations occur frequently in acute myeloid leukemia (AML), suggesting a functional role for Ras in leukemogenesis. biMethods /i/bWe successfully established a mouse model of human leukemia by transplanting bone marrow cells co-transfected with the K-ras (G12D) mutation and AML1/ETO fusion protein. biResults /i/bMice transplanted with AML/ETO+KRAS co-transduced cells had the highest mortality rate than mice transplanted with AML/ETO- or KRAS-transduced cells (115d vs. 150d). Upon reaching a terminal disease stage, EGFP-positive cells dominated their spleen, lymph nodes, peripheral blood and central nervous system tissue. Immunophenotyping, cytologic analyses revealed that AML/ETO+KRAS leukemias predominantly contained immature myeloid precursors (EGFPsup+/sup/c-Kitsup+/sup/Mac-1sup-/sup/Gr-1sup-/sup). Histologic analyses revealed that massive leukemic infiltrations were closely packed in dense sheets that effaced the normal architecture of spleen and thymus in mice transplanted with AML1/ETO + KRAS co-transduced cells. K-ras mRNA and protein expression were upregulated in bone marrow cells of the K-ras group and AML1/ETO + Kras group. The phosphorylation of MEK/ERK was significantly enhanced in the AML1/ETO + Kras group. The similar results of the AML1/ETO + Nras group were consistent with those reported previously. biConclusion /i/bCo-transduction of KrassupiG12D/i/sup and AML1/ETO induces acute monoblastic leukemia. Since expression of mutant K-ras alone was insufficient to induce leukemia, this model may be useful for investigating the multi-step leukemogenesis model of human leukemia.
机译：背景/目标 已证明 KRAS 突变约占癌症相关突变的90％，而 KRAS >突变在肿瘤转化中起重要作用。癌症相关的RAS突变在急性髓细胞性白血病（AML）中频繁发生，表明Ras在白血病发生中的功能性作用。 方法 我们通过移植经K-ras（G12D）突变和AML1 / ETO融合蛋白共转染的骨髓细胞，成功建立了人类白血病小鼠模型。 结果 与AML / ETO或KRAS共转染的小鼠相比，移植AML / ETO + KRAS共转染的小鼠的死亡率最高（115d vs. 150d ）。达到晚期疾病阶段后，EGFP阳性细胞占据了它们的脾脏，淋巴结，外周血和中枢神经系统组织。免疫表型分析，细胞学分析显示AML / ETO + KRAS白血病主要包含未成熟的髓样前体（EGFP + / c-Kit + / Mac-1 - / Gr-1 -）。组织学分析表明，大量白血病浸润紧密地堆积在致密的片中，从而影响了移植了AML1 / ETO + KRAS共转染细胞的小鼠的脾脏和胸腺的正常结构。在K-ras组和AML1 / ETO + Kras组的骨髓细胞中，K-ras mRNA和蛋白表达上调。在AML1 / ETO + Kras组中，MEK / ERK的磷酸化显着增强。 AML1 / ETO + Nras组的相似结果与以前报道的结果一致。 结论 Kras G12D 和AML1 / ETO的共转导诱导急性单细胞白血病。由于仅突变K-ras的表达不足以诱导白血病，因此该模型可用于研究人白血病的多步白血病发生模型。

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