Both human leukemia and lymphoma cells display de-repression of fetal and embryonic genes (Frenster JH and Herstein PR, 1973). The locale and number of the sites of gene de-repression within living or fixed bone marrow spicules or lymph nodes obtained from untreated patients were analyzed by a high-resolution ultrastructural molecular probe technique (Frenster JH, 1971; Frenster JH, 1972). The electron-dense reaction products indicating de-repressed DNA templates were found exclusively within the extended euchromatin portions of the cell nucleus. The number of such de-repressed gene sites per cell decreased with increasing degrees of differentiation of the leukemia or lymphoma cells. Normal or immune cells within the bone marrow or lymph node samples also showed a similar correlation of gene de-repression with the stage of cell differentiation. These quantitative ultrastructural data on intact human leukemia or lymphoma cells indicate that de-repressed DNA templates are closely correlated to de-differentiation of these cells in-vivo within untreated patients. Mitotic neoplastic leukemia and lymphoma cells similarly showed a reduced number of de-repressed DNA templates during late prophase, metaphase, anaphase, and early telophase, with a return toward normal numbers of de-repressed DNA templates during late telophase and early interphase. Recent data suggest that these de-repressed DNA templates within the extended euchromatin portion of the cell nucleus are the sites of single-stranded integration of oncogenic viral genomes, permitting de-repression of host genes at these sites of viral integration in animal and human neoplasms (Fig. 1).
Fig. 1. Oncogenic viral genomes contain base sequences complementary to sequences in the host genome DNA (Todaro GJ and Huebner RJ, 1972). Such viral DNA is capable of binding the anti-coding strand of the host DNA, freeing the coding strand of DNA for messenger RNA synthesis. Concurrently, the remaining strand of viral DNA is freed for anti-messenger RNA synthesis, and such RNA products are capable of forming RNA-RNA duplexes (Aloni Y and Locker H, 1973). Single-strand scissions of an unpaired DNA strand (IUDR, BUDR, radiation) result in liberation of the viral genome from the integrated state (Lowy DR, et al, 1971; Teich N, et al, 1973), and allow the previously-transformed cells to revert to normal phenotypic behaviour ( McPherson I, 1965; Nomura S, et al, 1973). Portions of the viral and host genomes not involved in DNA helix openings are not involved in RNA synthesis (Frenster JH and Herstein PR, 1973).
It is now necessary to explore the molecular details of such DNA helix openings and their control during such vital cellular processes as aging, oncogenesis, and the response to radiation (Kaplan HS and Howsden FL, 1964). A summary of such interactions is given in Fig. 2.
Fig. 2. Gene de-repression, whether induced by oncogenic viruses, physical or chemical carcinogens, or mitotic errors, plays a central role in human neoplastic disease (Frenster JH and Herstein PR, 1973). By virtue of persistent gene de-repression within neoplastic cells, an arrest in the normal maturation process occurs, allowing a continued high growth fraction of proliferating cells and a pronged individual cell life span with decreased death rates of individual cells. Such gene de-repression may also allow re-expression of fetal antigens in the neoplastic cells (Frenster JH and Herstein PR, 1973), with resultant immune responses in lymphocytes and macrophages (Frenster JH, et al, 1974). Neoplastic gene de-repression may also on occasion result in the ectopic synthesis by non-endocrine neoplasms of polypeptide hormones resulting in ectopic hormone syndromes (Frenster JH and Herstein PR, 1973).
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