Spatial proximity of translocation-prone gene loci in human lymphomas.
Cancer cells frequently have disease-specific chromosome rearrangements. It is poorly understood why translocations between chromosomes recur at specific breakpoints in the genome. Here we provide evidence that higher-order spatial genome organization is a contributing factor in the formation of recurrent translocations. We show that MYC, BCL and immunoglobulin loci, which are recurrently translocated in various B-cell lymphomas, are preferentially positioned in close spatial proximity relative to each other in normal B cells. Loci in spatial proximity are non-randomly positioned towards the nuclear interior in normal B cells. This locus proximity is the consequence of higher-order genome structure rather than a property of individual genes. Our results suggest that the formation of specific translocations in human lymphomas, and perhaps other tissues, is determined in part by higher-order spatial organization of the genome.
Roix
Jeffrey J
JJ
National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
McQueen
Philip G
PG
Munson
Peter J
PJ
Parada
Luis A
LA
Misteli
Tom
T
D004268:DNA-Binding Proteins / Q000235:genetics*; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*
D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors