Parikh Chaitali, Subrahmanyam Ramesh, Ren Ruibao
Rosenstiel Basic Medical Sciences Research Center, MS029, Brandeis University, Waltham, MA 02454-9110, USA.
Blood. 2006 Oct 1;108(7):2349-57. doi: 10.1182/blood-2004-08-009498. Epub 2006 Jun 8.
Activating mutations in RAS, predominantly NRAS, are common in myeloid malignancies. Previous studies in animal models have shown that oncogenic NRAS is unable to induce myeloid malignancies effectively, and it was suggested that oncogenic NRAS might only act as a secondary mutation in leukemogenesis. In this study, we examined the leukemogenicity of NRAS using an improved mouse bone marrow transduction and transplantation model. We found that oncogenic NRAS rapidly and efficiently induced chronic myelomonocytic leukemia (CMML)- or acute myeloid leukemia (AML)- like disease in mice, indicating that mutated NRAS can function as an initiating oncogene in the induction of myeloid malignancies. In addition to CMML and AML, we found that NRAS induced mastocytosis in mice. This result indicates that activation of the RAS pathway also plays an important role in the pathogenesis of mastocytosis. The mouse model for NRAS leukemogenesis established here provides a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing relevant therapies.
RAS基因（主要是NRAS）的激活突变在髓系恶性肿瘤中很常见。以往在动物模型中的研究表明，致癌性NRAS无法有效诱导髓系恶性肿瘤，有人提出致癌性NRAS可能仅在白血病发生过程中作为二次突变起作用。在本研究中，我们使用改进的小鼠骨髓转导和移植模型检测了NRAS的致白血病能力。我们发现致癌性NRAS能在小鼠中快速有效地诱导慢性粒单核细胞白血病（CMML）或急性髓系白血病（AML）样疾病，这表明突变的NRAS在髓系恶性肿瘤的诱导过程中可作为起始癌基因发挥作用。除了CMML和AML，我们还发现NRAS可诱导小鼠发生肥大细胞增多症。这一结果表明RAS信号通路的激活在肥大细胞增多症的发病机制中也起着重要作用。在此建立的NRAS白血病发生小鼠模型为进一步研究髓系恶性肿瘤发病机制的分子机制以及测试相关治疗方法提供了一个系统。
