Conditioned tumorigenicity of activated oncogenes.
Virally transduced oncogenes (v-onc) have a restricted target cell spectrum. They transform only a small part of the cell types in which they are expressed. Temperature-sensitive (ts) mutant studies have shown that some of them may act by blocking specific steps of maturation. If the cell can bypass the block, e.g., by a temporary switch off of the temperature-sensitive transforming protein, reexpression of the oncogene product at the permissive temperature may be unable to restore the transformed phenotype. Consideration of these facts, together with evidence concerning the reversion of the transformed phenotype and the suppression of tumorigenicity in hybrids derived from the fusion of normal and malignant cells, leads to the concept of "conditioned tumorigenicity." It states that the transforming and/or tumorigenic effect of a given oncogene, activated by structural or by regulatory changes, is restricted to specific and often quite narrow differentiation or maturation windows within each susceptible lineage. A similar restriction seems to apply to oncogenes activated by chromosomal translocation. The regular juxtaposition of the c-myc gene to one of the three immunoglobulin loci in Burkitt's lymphoma, mouse plasmacytoma, and rat immunocytoma is a case in point. The myc-carrying chromosome can break at many different places, within, upstream, or downstream of the gene, but not within its coding exons. This suggests that the break occurs at random and the myc protein plays an essential role in the selective, i.e., tumorigenic process. If so, other oncogenes should be equally transposable to the "Ig hot spots" during the long series of cell divisions in the preneoplastic target cell population that characterizes the prehistory of both BL and MPC. In other human B-cell leukemias and lymphomas, other (e.g., 11;14 and 14;18) translocations have been found, confirming that this can actually occur, but only in histologically different neoplasms. The exclusive involvement of myc in BL and MPC must be relatable to the specific functional features of the precursor cells and to the normal role of the myc protein. Recent evidence indicates that the myc gene is regularly turned off before or at the time when the cell enters a pathway that is programmed to lead it towards a resting Go state. Clonally expanded B-cells are believed to turn into resting memory cells upon waning of the antigenic stimulus. The normal, nontranslocated myc allele is regularly switched off in both BL and MPC, indicating that the cell has already obeyed a program involving the down-regulation of myc.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D002051:Burkitt Lymphoma / Q000235:genetics; D002454:Cell Differentiation; D005784:Gene Amplification; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D009369:Neoplasms / Q000503:physiopathology*; D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011519:Proto-Oncogenes; D011956:Receptors, Cell Surface / Q000502:physiology; D011995:Recombination, Genetic; D014178:Translocation, Genetic
D011956:Receptors, Cell Surface; D011505:Protein-Tyrosine Kinases