Rosenhahn Julia, Weise Anja, Michel Susanne, Hennig Katrin, Hartmann Isabell, Schiefner Jana, Schubert Katrin, Liehr Thomas, von Eggeling Ferdinand, Loncarevic Ivan F
Core Unit Chip Application, Institute of Human Genetics and Anthropology, Jena, Germany.
Int J Oncol. 2007 Jul;31(1):121-8.
Approximately 30% of chronic myeloid leukemia patients show initially no response to Imatinib, a potent inhibitor of BCR-ABL. This intrinsic resistance may be due to BCR-ABL-independent cell growth. Here we analysed the cytogenetic anomalies and the proteomic profiling in KCL22-S and KCL22-R, two Imatinib-sensitive and -resistant derivative cell lines of KCL22. A tetrasomy 8 and a non-reciprocal translocation +der(6)t(6;13)(p11.1;q12) were found only in KCL22-R as new evolved anomalies. Chromosome der(6)t(6;13) showed four variants differing in the chromatin content of 13q14-13qter including the retinoblastoma gene. Due to these sub-clones, approximately 65-79% of the Imatinib-treated KCL22-R cells showed a disomy and 21-35% a monosomy for 13q14. Imatinib removal reduced the main clone to approximately 20% in the benefit of the monosomic sub-clones. This was accompanied by an increased apoptosis rate and was revertible by Imatinib re-treatment. This effect may be connected with genes located in 13q14-qter. Proteomic profiling of the cell lines performed with ProteinChip technology (SELDI) revealed several differentially expressed proteins (n=45). In summary, we demonstrate here the complex changes on the cytogenetic and proteomic level which could be caused by Imatinib and the resistance resulting from it.
大约30%的慢性髓性白血病患者最初对伊马替尼（一种有效的BCR-ABL抑制剂）无反应。这种内在抗性可能归因于不依赖BCR-ABL的细胞生长。在此，我们分析了KCL22-S和KCL22-R这两种KCL22的伊马替尼敏感和抗性衍生细胞系中的细胞遗传学异常和蛋白质组学图谱。仅在KCL22-R中发现了8号染色体四体和一种非相互易位+der(6)t(6;13)(p11.1;q12)作为新出现的异常。染色体der(6)t(6;13)显示出四种变体，它们在包括视网膜母细胞瘤基因在内的13q14 - 13qter的染色质含量上有所不同。由于这些亚克隆，大约65 - 79%接受伊马替尼治疗的KCL22-R细胞显示13q14为二体，21 - 35%为单体。去除伊马替尼后，主要克隆减少到约20%，有利于单体亚克隆。这伴随着凋亡率的增加，并且通过重新给予伊马替尼可逆转。这种效应可能与位于13q14 - qter的基因有关。使用蛋白质芯片技术（SELDI）对细胞系进行的蛋白质组学图谱分析揭示了几种差异表达的蛋白质（n = 45）。总之，我们在此证明了伊马替尼可能导致的细胞遗传学和蛋白质组学水平上的复杂变化以及由此产生的抗性。
