Horiike S, Misawa S, Nakai H, Kaneko H, Yokota S, Taniwaki M, Yamane Y, Inazawa J, Abe T, Kashima K
Department of Internal Medicine, III, Kyoto Prefectural University of Medicine, Japan.
Leukemia. 1994 Aug;8(8):1331-6.
We performed a longitudinal analysis of the karyotypes and N-ras gene configuration of bone marrow cells in 35 patients with myelodysplastic syndrome (MDS). Karyotypic evolution was found in eight patients, and was associated with disease progression, including leukemic transformation, in all the patients. We identified N-ras mutations in six patients, using a polymerase chain reaction (PCR) technique, in which oligonucleotide primers were constructed with induced mismatches, followed by endonuclease digestion. Direct sequencing confirmed single base substitutions at codon 12 in two patients and at codon 13 in four. The incidence of N-ras gene mutations was significantly higher in the karyotypically evolved group (five of eight patients) than in the stable group (one of 27 patients). All of five patients harboring both karyotypic evolution and an N-ras mutation showed concomitant disease progression to overt leukemia or refractory anemia with excess of blasts in transformation (RAEB-T). Two of four patients with either karyotypic evolution or N-ras mutation and six of 26 patients without any of these alterations also progressed to overt leukemia. Our results indicate that the accumulation of these genetic alterations is closely associated with leukemic transformation of MDS, although other genetic alterations may also play a key role in the remaining patients.
我们对35例骨髓增生异常综合征（MDS）患者的骨髓细胞进行了核型和N-ras基因结构的纵向分析。在8例患者中发现了核型演变，且所有这些患者的核型演变均与疾病进展相关，包括白血病转化。我们使用聚合酶链反应（PCR）技术，构建诱导错配的寡核苷酸引物，然后进行核酸内切酶消化，在6例患者中鉴定出N-ras突变。直接测序证实，2例患者密码子12处发生单碱基替换，4例患者密码子13处发生单碱基替换。核型演变组（8例患者中的5例）的N-ras基因突变发生率显著高于稳定组（27例患者中的1例）。所有同时具有核型演变和N-ras突变的5例患者均显示疾病进展为明显白血病或转化中的原始细胞过多难治性贫血（RAEB-T）。4例具有核型演变或N-ras突变的患者中的2例以及26例无任何这些改变的患者中的6例也进展为明显白血病。我们的结果表明，这些基因改变的积累与MDS的白血病转化密切相关，尽管其他基因改变在其余患者中可能也起关键作用。
