Parikh Chaitali, Ren Ruibao
Rosenstiel Basic Medical Sciences Research Center, Department of Biology, Brandeis University, Waltham, Massachusetts, USA.
Methods Enzymol. 2008;439:15-24. doi: 10.1016/S0076-6879(07)00402-8.
Mutations that result in constitutive activation of RAS proteins are common in human hematological malignancies. In addition, functional activation of the RAS pathway can occur in leukemias, either due to mutations in genes that code for proteins upstream of RAS or due to inactivation of negative regulators of RAS. However, despite this prominent association of RAS activation with human leukemias, its precise role in leukemogenesis is not known. Previous studies have met with limited success in developing relevant animal models for leukemogenesis by oncogenic NRAS, the most frequently mutated RAS gene in human leukemias, and have suggested that oncogenic RAS might only act as a secondary event in leukemogenesis. This chapter describes an efficient and relevant murine model for myeloid leukemias initiated by oncogenic NRAS using an improved bone marrow transduction/transplantation system. This model provides a system for further studying the molecular mechanisms in the pathogenesis of myeloid malignancies and for testing targeted therapies.
导致RAS蛋白组成型激活的突变在人类血液系统恶性肿瘤中很常见。此外，RAS信号通路的功能激活可发生于白血病中，这要么是由于编码RAS上游蛋白的基因突变，要么是由于RAS负调控因子的失活。然而，尽管RAS激活与人类白血病有着显著关联，但其在白血病发生中的精确作用尚不清楚。以往的研究在通过致癌性NRAS（人类白血病中最常发生突变的RAS基因）建立相关白血病发生动物模型方面取得的成功有限，并表明致癌性RAS在白血病发生中可能仅作为继发事件起作用。本章描述了一种使用改进的骨髓转导/移植系统，由致癌性NRAS引发的髓系白血病的高效且相关的小鼠模型。该模型为进一步研究髓系恶性肿瘤发病机制中的分子机制以及测试靶向治疗提供了一个系统。
