Müller A M S, Duque J, Shizuru J A, Lübbert M
Department of Hematology/Oncology, University Medical Center Freiburg, Baden Wuerttemberg, Freiburg, Germany.
Oncogene. 2008 Oct 2;27(44):5759-73. doi: 10.1038/onc.2008.196. Epub 2008 Jul 7.
A great proportion of acute myeloid leukemias (AMLs) display cytogenetic abnormalities including chromosomal aberrations and/or submicroscopic mutations. These abnormalities significantly influence the prognosis of the disease. Hence, a thorough genetic work-up is an essential constituent of standard diagnostic procedures. Core binding factor (CBF) leukemias denote AMLs with chromosomal aberrations disrupting one of the CBF transcription factor genes; the most common examples are translocation t(8;21) and inversion inv(16), which result in the generation of the AML1-ETO and CBFbeta-MYH11 fusion proteins, respectively. However, in murine models, these alterations alone do not suffice to generate full-blown leukemia, but rather, complementary events are required. In fact, a substantial proportion of primary CBF leukemias display additional activating mutations, mostly of the receptor tyrosine kinase (RTK) c-KIT. The awareness of the impact and prognostic relevance of these 'second hits' is increasing with a wider range of mutations tested in clinical trials. Furthermore, novel agents targeting RTKs are emanating rapidly and entering therapeutic regimens. Here, we present a concise review on complementing mutations in CBF leukemias including pathophysiology, mouse models, and clinical implications.
很大一部分急性髓系白血病（AML）表现出细胞遗传学异常，包括染色体畸变和/或亚显微突变。这些异常显著影响疾病的预后。因此，全面的基因检测是标准诊断程序的重要组成部分。核心结合因子（CBF）白血病是指染色体畸变破坏其中一个CBF转录因子基因的AML；最常见的例子是易位t(8;21)和倒位inv(16)，它们分别导致AML1-ETO和CBFβ-MYH11融合蛋白的产生。然而，在小鼠模型中，仅这些改变不足以引发全面的白血病，而是需要互补事件。事实上，相当一部分原发性CBF白血病表现出额外的激活突变，主要是受体酪氨酸激酶（RTK）c-KIT的突变。随着临床试验中检测的突变范围更广，对这些“二次打击”的影响和预后相关性的认识也在增加。此外，针对RTK的新型药物正在迅速涌现并进入治疗方案。在此，我们对CBF白血病中的互补突变进行简要综述，包括病理生理学、小鼠模型和临床意义。
