ABSTRACT
It is believed that two important factors in the genesis of reciprocal chromosomal translocations in malignant cells are the physical proximity of the involved regions and local structural features of the chromatin fiber that make them more susceptible to breakage and rearrangement. In this work we sought to investigate whether PML-RARA fusion transcripts, characteristic of acute promyelocytic leukemia (APL), could be induced by a clastogenic agent in cells known to have, a priori, a favorable spatial distribution of these genes. A lymphoid-cell line, lacking the t(15;17) but having the PML and RARA genes in close proximity in specific phases of the cell cycle, was irradiated with 10 Gy of (60)Co, and the incidence of PML-RARA transcripts was analyzed by a highly sensitive PCR assay. Despite gene proximity, typical PML-RARA transcripts were only rarely detected in irradiated cells. The same phenomenon was observed at similar frequency in control non-irradiated cells. These findings made us investigate whether such transcripts could also be detected in peripheral blood cells from normal individuals. PML-RARA transcripts were observed at low frequencies in isolated lymphoid and granulocytic cell populations, with similar incidence in both cell types. The data thus indicate that the PML and RARA genes are not particularly susceptible to the clastogenic effects of gamma-irradiation, and that, similar to what has been reported for other chromosomal translocations, transcriptionally active PML-RARA rearrangements can be generated in normal hematopoietic cells of different lineages without apparent oncogenic consequences.
Subject(s)
Hematopoietic Stem Cells/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/radiation effects , Nuclear Proteins , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/radiation effects , Receptors, Retinoic Acid/genetics , Receptors, Retinoic Acid/radiation effects , Transcription Factors/genetics , Transcription Factors/radiation effects , Chromosome Aberrations/etiology , Chromosome Disorders , Gamma Rays/adverse effects , Hematopoietic Stem Cells/radiation effects , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/metabolism , Mutation , Promyelocytic Leukemia Protein , Recombination, Genetic/radiation effects , Retinoic Acid Receptor alpha , Tumor Cells, Cultured/metabolism , Tumor Cells, Cultured/radiation effects , Tumor Suppressor ProteinsABSTRACT
We report here that ultraviolet irradiation substantially reduced the mRNA and protein of the two major nuclear retinoid receptors, RAR-gamma and RXR-alpha, in human skin in vivo. Pre-treatment with retinoic acid mitigated this loss of nuclear retinoid receptors. Ultraviolet irradiation caused a near-total loss of retinoic acid induction of two RAR/RXR target genes, cellular retinoic acid binding protein-II and RA 4-hydroxylase, but did not affect 1,25-dihydroxyvitamin D3 induction of the vitamin D receptor/RXR-regulated gene vitamin D 24-hydroxylase. In effect, ultraviolet irradiation causes a functional vitamin A deficiency that may have deleterious effects on skin function, contributing to skin photo-aging and carcinogenesis.
