Greenberger J S
Department of Radiation Oncology, University of Massachusetts Medical Center, Worcester 01655.
Int J Cell Cloning. 1989 Nov;7(6):343-59. doi: 10.1002/stem.5530070603.
The clinical association of an increased incidence of acute myelogenous leukemia (AML) with previous chemoradiotherapy, the detection of specific karyotypic changes in these secondary (therapy-induced) cases of AML and the discovery of increasing levels of oncogene-specific RNA in leukemia cells suggest that one potential site of action of environmental agents might be the proto-oncogenes in human hematopoietic stem cells. The location of human proto-oncogenes at the sites of chromosome breaks and/or translocations in cells from some patients with leukemia or lymphoma is a striking observation. These data stimulated research into the mechanism of activation of specific oncogenes that change the biology of human hematopoietic cells. Recent investigations have focused upon several areas that might alter cell biology including: 1) translocation and/or inversion of chromosome fragments containing a proto-oncogene to a location where other gene sequences can stimulate oncogene activation, 2) replication of copy number of proto-oncogenes or increased transcriptional activity and 3) point mutation in proto-oncogenes leading to a structurally altered protein. The third area of research has recently received significant attention with respect to the potential role of three ras genes (c-Harvey-ras, c-Kirsten-ras and N-ras) in human leukemias and myelodysplastic syndromes. Recent studies have proposed a model for leukemogenic transformation of human hematopoietic cells by the product of a mutated ras oncogene. Mutations at codons 12, 13 or 61 of the first exon of its 4.7 Kb of DNA (for c-Ha-ras) have been described. Other data revealing an absence of such mutations in the ras genes of many human leukemias and the absence of detectable transcription of ras genes in many alkylating agent-associated cases of AML, suggest that while ras mutations may be involved in some settings, there are probably multiple genetic pathways to leukemogenic transformation of human hematopoietic cells.
急性髓性白血病（AML）发病率增加与既往放化疗之间的临床关联、在这些继发性（治疗诱导性）AML病例中检测到的特定核型变化以及白血病细胞中癌基因特异性RNA水平的不断升高表明，环境因素的一个潜在作用位点可能是人类造血干细胞中的原癌基因。人类原癌基因位于某些白血病或淋巴瘤患者细胞中染色体断裂和/或易位的位点，这是一个引人注目的观察结果。这些数据激发了对改变人类造血细胞生物学特性的特定癌基因激活机制的研究。最近的研究集中在几个可能改变细胞生物学特性的领域，包括：1）包含原癌基因的染色体片段易位和/或倒位至其他基因序列可刺激癌基因激活的位置；2）原癌基因拷贝数的复制或转录活性增加；3）原癌基因中的点突变导致蛋白质结构改变。关于三种ras基因（c-Harvey-ras、c-Kirsten-ras和N-ras）在人类白血病和骨髓增生异常综合征中的潜在作用，第三个研究领域最近受到了极大关注。最近的研究提出了一个由突变的ras癌基因产物导致人类造血细胞白血病转化的模型。已描述了其4.7 Kb DNA（对于c-Ha-ras）第一外显子密码子12、13或61处的突变。其他数据显示，许多人类白血病的ras基因中不存在此类突变，并且在许多与烷化剂相关的AML病例中未检测到ras基因的转录，这表明虽然ras突变可能在某些情况下起作用，但人类造血细胞白血病转化可能存在多种遗传途径。
