ABSTRACT
Deletions or monosomy of chromosomes 5 and 7 are frequently observed in myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). In this study two genes, PURA and PURB, encoding functionally cooperative proteins in the Pur family, are localized to chromosome bands 5q31.1 and 7p13, respectively. One or both of these loci are shown to be hemizygously deleted in 60 MDS or AML patients using fluorescence in situ hybridization (FISH). High-resolution mapping of PURA localizes it approximately 1.1 Mb telomeric to the EGR-1 gene. Frequency of PURA deletion and segregation with EGR-1 indicate that PURA is within the most commonly deleted segment in myeloid disorders characterized by del(5)(q31). No mutations have been detected within the coding sequence of PURA. Concurrent deletions of PURA and PURB occur in MDS at a rate nearly 1.5-fold higher than statistically expected and in AML at a rate > 5-fold higher. This novel simultaneous deletion of two closely related gene family members may thus have consequences related to progression to AML. Pur alpha, an Rb-binding protein, has been implicated in cell cycle control and differentiation, and Pur alpha and Pur beta are reported to function as heterodimers. Alterations in these genes could affect a delicate balance critical in myeloid development.
Subject(s)
Chromosomes, Human, Pair 5/genetics , Chromosomes, Human, Pair 7/genetics , Cyclic AMP Response Element-Binding Protein/genetics , DNA-Binding Proteins/deficiency , Gene Deletion , Immediate-Early Proteins , Leukemia, Myeloid/genetics , Myelodysplastic Syndromes/genetics , Acute Disease , Adult , Aged , Aged, 80 and over , Cell Transformation, Neoplastic/genetics , Child, Preschool , Chromosome Aberrations , Chromosome Deletion , Chromosome Mapping , Chromosomes, Artificial, Bacterial , DNA, Neoplasm/genetics , DNA-Binding Proteins/genetics , Disease Progression , Early Growth Response Protein 1 , Female , Gene Library , Genotype , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Leukemia, Myeloid/pathology , Loss of Heterozygosity , Male , Microsatellite Repeats , Middle Aged , Myelodysplastic Syndromes/pathology , Neoplasm Proteins/deficiency , Neoplasm Proteins/genetics , Nerve Tissue Proteins , Polymerase Chain Reaction , Transcription Factors/deficiency , Transcription Factors/genetics , Translocation, GeneticABSTRACT
Asbestos fibers are widespread environmental carcinogens whose mutagenicity is now established. Nonetheless, the molecular nature of these mutations and the mechanisms by which they accelerate carcinogenesis remain poorly understood. We have assessed the ability of asbestos fibers to promote homologous recombination, a potent mechanism for generating intrachromosomal rearrangements, such as deletions, and mitotic recombination. For this, we have developed a new assay which determines the extent to which a marker gene present in DNA introduced by asbestos can recombine with homologous genes residing in a transfected cell. We have demonstrated that Calidria chrysotile fibers are mutagenic and are able to mediate transfection of molecularly marked mutant lacI genes in a manner that results in their preferential recombination with homologous wild-type genes in the transfected cell. Asbestos induced recombination events may play a significant role in asbestos mutagenesis and carcinogenesis, and promotion of recombination may underlie the well-recognized synergy of asbestos with other carcinogens.
