Saha Vaskar, Young Bryan D, Freemont Paul S
Imperial Cancer Research Fund, Department of Medical Oncology, St Bartholomew's Hospital, London EC1A 6BQ, UK.
Molecular Structure and Function Laboratory, London WC2A 3PX, UK.
J Cell Biochem. 1998;72 Suppl 30-31(S30-31):264-276. doi: 10.1002/(SICI)1097-4644(1998)72:30/31+<264::AID-JCB32>3.0.CO;2-U.
Genes involved in chromosomal translocations, associated with the formation of fusion proteins in leukemia, are modular in nature and regulatory in function. It is likely that they are involved in the initiation and maintenance of normal hematopoiesis. A conceptual model is proposed by which disruption of these different genes leads to the development of acute leukemia. Central to this model is the functional interaction between the mammalian trithorax and polycomb group protein complexes. Many of the genes identified in leukemia-associated translocations are likely upstream regulators, co-participators or downstream targets of these complexes. In the natural state, these proteins interact with each other to form multimeric higher-order structures, which sequentially regulate the development of the normal hematopoietic state, either through HOX gene expression or other less defined pathways. The novel interaction domains acquired by the chimaeric fusion products subvert normal cellular control mechanisms, which result in both a failure of cell maturation and activation of anti-apoptotic pathways. The mechanisms by which these translocation products are able to affect these processes are thought to lie at the level of chromatin-mediated transcriptional activation and/or repression. The stimuli for proliferation and development of clinically overt disease may require subsequent mutations in more than one oncogene or tumor suppressor gene, or both. A more comprehensive catalogue of mutation events in malignant cells is therefore required to understand the key regulatory networks that serve to maintain multipotentiality and in particular the modifications which initiate and coordinate commitment in differentiating hematopoietic cells. We propose a model in which common pathways for leukemogenesis lie along the cell cycle control of chromatin structure in terms of transcriptional activation or repression. A clearer understanding of this cascade will provide opportunities for the design and construction of novel biological agents that are able to restore normal regulatory mechanisms. J. Cell. Biochem. Suppls. 30/31:264-276, 1998. © 1998 Wiley-Liss, Inc.
参与染色体易位、与白血病中融合蛋白形成相关的基因，本质上是模块化的，功能上是调节性的。它们很可能参与正常造血的起始和维持。本文提出了一个概念模型，据此这些不同基因的破坏会导致急性白血病的发生。该模型的核心是哺乳动物三胸蛋白和多梳蛋白家族蛋白复合物之间的功能相互作用。在白血病相关易位中鉴定出的许多基因可能是这些复合物的上游调节因子、共同参与者或下游靶点。在自然状态下，这些蛋白质相互作用形成多聚体高阶结构，通过HOX基因表达或其他不太明确的途径依次调节正常造血状态的发展。嵌合融合产物获得的新相互作用结构域颠覆了正常的细胞控制机制，导致细胞成熟失败和抗凋亡途径激活。这些易位产物影响这些过程的机制被认为在于染色质介导的转录激活和/或抑制水平。临床显性疾病增殖和发展的刺激因素可能需要一个以上原癌基因或肿瘤抑制基因，或两者的后续突变。因此，需要一个更全面的恶性细胞突变事件目录，以了解维持多能性的关键调控网络，特别是启动和协调造血细胞分化过程中的修饰。我们提出了一个模型，其中白血病发生的共同途径在于染色质结构的细胞周期控制，涉及转录激活或抑制。对这一级联反应的更清晰理解将为设计和构建能够恢复正常调节机制的新型生物制剂提供机会。《细胞生物化学杂志》增刊30/31:264 - 276，1998年。©1998威利 - 利斯公司。
