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Translocations, fusion genes, and acute leukemia
Author(s) -
Saha Vaskar,
Young Bryan D.,
Freemont Paul S.
Publication year - 1998
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/(sici)1097-4644(1998)72:30/31+<264::aid-jcb32>3.0.co;2-u
Subject(s) - biology , chromosomal translocation , chromatin , fusion gene , gene , haematopoiesis , leukemia , genetics , polycomb group proteins , microbiology and biotechnology , fusion protein , transcription factor , cancer research , stem cell , repressor , recombinant dna
Abstract 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.