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Conditioned Tumorigenicity of Activated Oncogenes¹

Department of Tumor Biology, Karolinska Institutet, S-104 01 Stockholm, Sweden and Department of Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel

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 G₀ 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. The Ig-juxtaposed, translocated myc remains highly expressed, however, and may be responsible for keeping the cells in cycle. The possibility that BL and MPC may arise from candidate memory cells, rather than pre-B-cells, is also suggested by the fact that all BL tumors and derived lines make a heavy chain. Since the myc/Ig juxtaposition is a special case of a nonfunctional rearrangement, this is expected only if the precursor cell would have been preselected for a functional Ig product. The memory cell is further incriminated by the fact that the majority of BLs make IgM; most MPCs produce IgA; and rat immunocytomas, known to arise in parasite-infested Louvain rats, make IgE.

¹ Dedicated to the memory of Jacob Furth.

Received 11/12/85. Accepted 1/28/86.

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