Nowak Daniel, Mossner Maximilian, Baldus Claudia D, Hopfer Olaf, Thiel Eckhard, Hofmann Wolf-Karsten
Department of Hematology, Oncology and Transfusion Medicine, Charité, University Hospital Benjamin Franklin, Berlin, Germany.
Int J Med Sci. 2006 Oct 26;3(4):148-51. doi: 10.7150/ijms.3.148.
hCDC4 (FBW7, FBXW7) is a new potential tumor suppressor gene which provides substrate specificity for SCF (Skp-Cullin-F-box) ubiquitin ligases and thereby regulates the degradation of potent oncogenes such as cyclin E, Myc, c-Jun and Notch. Mutations in the hCDC4 gene have been found in several solid tumors such as pancreas, colorectal or endometrial cancer. We carried out a mutation analysis of the hCDC4 gene in 35 samples of patients with Acute Myeloid Leukemia (AML) to elucidate a possible role of hCDC4 mutations in this disease. By direct DNA sequencing and digestion with Surveyor nuclease one heterozygous mutation in the 5' untranslated region of exon 1, transcript variant 3 was detected. Additionally, we could identify a new intronic SNP downstream of exon 10. The new variation was present in 20% of AML samples and was furthermore confirmed in a panel of 51 healthy individuals where it displayed a frequency of 14%. In conclusion we provide first data that in contrast to several solid tumors, mutations in the hCDC4 gene may not play a pivotal role in the pathogenesis of AML. Furthermore, we describe a new intronic polymorphism with high frequency in the intron sequence of the hCDC4 gene.
人源CDC4（FBW7、FBXW7）是一种新的潜在肿瘤抑制基因，它为SCF（Skp-接头蛋白-Cullin-F盒）泛素连接酶提供底物特异性，从而调节细胞周期蛋白E、Myc、c-Jun和Notch等强效癌基因的降解。在胰腺癌、结直肠癌或子宫内膜癌等几种实体瘤中已发现人源CDC4基因突变。我们对35例急性髓系白血病（AML）患者样本进行了人源CDC4基因突变分析，以阐明人源CDC4基因突变在该疾病中的可能作用。通过直接DNA测序和Surveyor核酸酶消化，在转录变体3的外显子1的5'非翻译区检测到一个杂合突变。此外，我们在第10外显子下游发现了一个新的内含子单核苷酸多态性（SNP）。这种新变异存在于20%的AML样本中，并且在一组51名健康个体中得到进一步证实，其频率为14%。总之，我们提供的初步数据表明，与几种实体瘤不同，人源CDC4基因突变可能在AML发病机制中不发挥关键作用。此外，我们描述了一种在人源CDC4基因内含子序列中高频出现的新内含子多态性。
