Leukemia Viruses

A Bumy1-2, F Bex2, F Dequiedt1, E Adam1, JS Gatot1, P Kerkhofs3, R Kettmann1, O Porteteile1, A Van Den Broeke2 and L Willems1, 1Gembloux Faculté Universitaire des Sciences Agronomiques, 2University of Brussels and 3National Institute for Veterinary Research, Belgium

Leukemia is a cancer of blood-forming cells. It can be caused by viruses in humans (adult T cell leukemia) as in animals (mice, cats, cattle, birds, etc.). All known leukemia-inducing viruses belong to the subfamily Oncovirinae of the family Retroviridae. Other retroviruses include the lentiviruses, a subfamily of pathogenic slowviruses (the AIDS viruses, for example) and the spumaviruses or foamy viruses that cause persistent infections without clinical disease.

The oncoviruses (Gr. onkos, mass, bulk) include viruses that infect target cells and lead to their transformation; that is, the virus creates a tumor-producing potential in infected cells. Transformation can occur as an acute phenomenon; it then leads to polyclonal tumors (like myelomonocytosis induced in the chicken by the avian leukemia virus, MC29). When transformation occurs as a chronic phenomenon, it is a very rare event (1 cell out of 10'°-1015 for example). Tumors that develop in the animal are mono- or oligoclonal. They derive from a single (or very few) transformed cell(s).

Acutely transforming retroviruses carry v-onc sequences derived from the host proto-oncogenes (c-onc sequences).

Conditional and nonconditional mutations affecting oncogenic properties of the virus have been mapped to the one sequences. They code for all or part of the transforming protein; they are not involved in virus replication and are, in most cases, devoid of intron sequences. The latter observation suggests that the recombination event that leads to integration of cellular information occurred as a postsplicing event of the RNA transcript. It could be that recombination took place at the reverse transcription step by a copy choice mechanism. As a consequence, the one information replaces information needed for viral replication and all acutely transforming leukemia viruses known today are replication-defective. They need a nondefective helper for propagation and have been considered as laboratory curiosities rather than widespread pathogens. All however, were isolated from the field.

Nonacutely transforming viruses (inducers of leukemia after a long latency period) carry the information necessary for virus replication. Their oncogenicity is due either to their site of integration in the target cell (avian leukosis virus, ALV; Moloney leukemia virus, MoLV) or to the activity of transactivating proteins that strongly activate virus replication but, at the same time, perturb regulatory circuits that control cell division and/or differentiation (human T lymphotropic virus type I; bovine leukemia virus).

The clinical experience in humans and the experimental data obtained in animals indicate that the development of leukemia is a multistep process. One thus expects that oncogene activation via viral infection is only one step in a cascade. In acute transformation, activation of the whole cascade is a short-duration process. In contrast, infection by nonacutely transforming viruses is supposed to only affect minor determinants of the neoplastic process. A long chronic stimulation is required before overt leukemia appears. Moreover, there are grades in the level of oncogenicity achieved by a given transformed cell. Indeed, DNA transfection experiments suggest that some oncogenes are not able to induce complete neoplastic transformation. However, frank oncogenicity can be achieved if two oncogenes are introduced in the same cell, acting in concert, presumably expressing complementary functions.

Viral carcinogenesis studies have amply demon strated that mechanisms leading to cancer include the following five processes:

1. Overexpression of a viral one gene.

2. Capture of a proto-oncogene (c-one) in a retroviral vector and appearance of mutations in the captured gene that make it highly oncogenic (v-onc).

3. Combination of two cooperating v-oncs in the same provirus.

4. Cooperation between a viral protein and activation of a c-one.

5. Reorganization of the cellular transcriptional processes by a viral transactivation protein.

Overexpression of a viral one gene

In this case, v-onc and c-one have identical sequences; v-onc is overexpressed due to its viral regulatory environment. Examples include insertion of myc in the avian leukemia virus MC29, and in the feline leukemia virus. An analogous state of overexpression can be created if a provirus is inserted upstream of c-onc and serves as a strong promoter via its 3' I.TR (long terminal repeat). Such a situation is known as 'downstream promotion' of expression. Examples of this situation include a majority of lymphomas induced by Moloney murine leukemia virus and a minority of the chicken lymphomas induced by RAV-l or ALV.

The Rous-associated virus type l (RAV-l), a helper virus that does not carry any oncogene, induces over-expression of myc and B cell lymphomas in chickens of the SPAFAS genetic background. The same helper promotes high expression of erbV> and induces erythroblastic leukemia in chickens of the line 15 1. Obviously host-virus interplay is fundamental in the type of neoplasm induced by the incoming virus. In most cases of downstream promotion, the integrated provirus has lost the 5' part of its genome; transcription starts from the 3' LTR and extends over the neighboring proto-oncogene.

A similar case of overexpression occurs when the enhancing provirus gets inserted downstream of the activated c-one, irrespective of the relative orientations of the provirus and the activated gene. This situation is known as 'regional activation' or 'proviral enhancement'. Regional activation can occur through chromosome breaks, translocations, deletions, insertions, amplifications caused by radiation, chemicals, or just by accident. Many examples of this situation have been described in human leukemia.

Capture of a proto-oncogene (c-onc) in a retroviral vector and appearance of mutations in the captured gene that make it highly oncogenic (v-onc)

Examples are numerous and include the one genes v-src (Rous sarcoma virus), v-myb (avian mvelo-

blastosis virus) and v-abl (Abelson murine leukemia virus). Expression of the encoded protein is a prerequisite to transformation of the target cell and maintenance of the transformed state. Animals that carry tumors caused by such viral agents develop antibodies to the v-onc protein (even though it derives from a normal cell constituent playing a role in cell proliferation or cell differentiation).

Combination of two cooperating v-oncs in the same provirus

The fact that two active oncogenes may cooperate to confer a growth advantage on the transformed cell is illustrated by the genetic structure of three avian acute leukemia viruses: AEV, with erbk (c-erbk is the receptor for thyroid hormone) and erbi> (c-erbB is the receptor for EGF, epidermal growth factor); E26, with myb and ets (the functions of c-myb and c-ets arc not well characterized yet); and MH2, with myc and mil (mil is homologous to the oncogene raf, found in the murine sarcoma virus 3611). The myc, myb and erbR genes have been identified separately in other viral isolates as the sole transforming gene. In each case, however, the virus with two oncogenes induces a more pronounced or advanced state of transformation than its counterpart with a single oncogene. In fact, refined experimental systems show that the six v-oncs - myc, myb, mil, ets, erbk and erbE - are all separately transforming. Their association in a given virus or their coexpression in a single target cell reinforces the transformed state as appreciated by characteristics such as requirement of specialized culture conditions, colony induction in semisolid medium, requirement for complex liquid medium for proliferation of cells explanted from colonies, and degree of spontaneous differentiation within colonies.

Cooperation between a viral protein and activation of a c-one

The viral protein acts as a mitogen The Friend erythroleukemia is induced in mice by a virus complex containing the defective spleen focus-forming virus (SFFV) and a helper murine leukemia virus. The SFFV envelope gene encodes a membrane glycoprotein, gp55. When expressed at the surface of murine eryth-roblasts, gp55 is highly mitogenic. It has no effect when it has lost its transmembrane anchor. The first consequence of infection is therefore polyclonal erythroblastosis that leads, however, to cell differentiation and recovery unless the helper is present and contributes to the production of more and more virus particles. Among the numerous integration events, one might concern the Spi-1 site (Spi for SFFV provirus integration site; the Spi-1 product is a transcriptional factor), a site linked with immortalization and tumor onset. Spi-1 is a presumptive oncogene. Enhanced transcription of Spi-1 follows SFFV integration in the vicinity. The Friend erythroleukemia system combines a mitogenic effect mediated via gp55 at the cell membrane and an insertional activation through enhanced transcription of Spi-1.

Overexpression of a growth factor Another model of cooperation between oncogenes uses myc-\mmor-talized monocytes. The cells are superinfected in vitro with a CSF-1 (colony stimulating factor)-expressing retrovirus. The result is a strong promotion of tumori-genesis. In this simple model, only two oncogenic activations are required for monocyte/macrophage transformation: immortalization of the cells with c-myc and deregulation of the CSF-I gene. However, not all mechanisms that result in loss of CSF-1 dependence lead to full tumorigenicity, suggesting that, in vivo, tumorigenesis may involve multiple secondary events including growth factor independence. Analogous experiments have shown that activation of the macrophage colony-stimulating factor (M-CSF) gene is a secondary event leading to the development of tumors in mononuclear phagocytic cells that have first been immortalized with the v-fms oncogene, (fms is the v-onc found in the McDonough strain of feline sarcoma virus; c-fms is the receptor for CSF-1 ).

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