Abstract
Specific chromosomal translocations are hallmarks of many human leukemias. The basis for these translocation events is poorly understood, but it has been assumed that spatial positioning of genes in the nucleus of hematopoietic cells is a contributing factor. Analysis of the nuclear 3D position of the gene MLL, frequently involved in chromosomal translocations and five of its translocation partners (AF4, AF6, AF9, ENL and ELL), and two control loci revealed a characteristic radial distribution pattern in all hematopoietic cells studied. Genes in areas of high local gene density were found positioned towards the nuclear center, whereas genes in regions of low gene density were detected closer to the nuclear periphery. The gene density within a 2 Mbp window was found to be a better predictor for the relative positioning of a genomic locus within the cell nucleus than the gene density of entire chromosomes. Analysis of the position of MLL, AF4, AF6 and AF9 in cell lines carrying chromosomal translocations involving these genes revealed that the position of the normal genes was different from that of the fusion genes, and this was again consistent with the changes in local gene density within a 2 Mbp window. Thus, alterations in gene density directly at translocation junctions could explain the change in the position of affected genes in leukemia cells.
Original language | English (US) |
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Pages (from-to) | 14-26 |
Number of pages | 13 |
Journal | Experimental Cell Research |
Volume | 311 |
Issue number | 1 |
DOIs | |
State | Published - Nov 15 2005 |
Funding
We thank Drs. Pamela Strissel, Reiner Strick, Markus O. Scheuermann, James Fackenthal and Isabelle Lucas for their helpful comments. We are grateful to Dr. Michael J. Thirman for his help in locating cell lines and identification of clones for the genes ENL and ELL . We thank Dr. Michelle LeBeau for making the 11365 cell line available for this project, Aparna Palakodeti for sharing her expertise in synchronization of 11365 cells and Yanwen Jiang for sharing his mathematical knowledge. This research was supported by National Institutes of Health/National Cancer Institute Grants CA 40046 and CA 84405 (both to J.D.R.) and the G. Harold and Leila Y. Mathers Charitable Foundation (to J.D.R.) and by the Deutsche Forschungsgemeinschaft (DFG Li 406/5-3).
Keywords
- Gene density
- MLL
- Nuclear organization
- Translocation
ASJC Scopus subject areas
- Cell Biology