Oncogenes in chronic lymphocytic leukemia

Oncogenes, in the context of retroviruses, are a common cause of leukemia in animals. Recently, activation of cellular oncogenes has been shown to be associated with leukemia in humans. Relatively few studies of oncogene activation in chronic lymphocytic leukemia (CLL) have been reported. In most instances, rearrangement of oncogenes has not been detected. Exceptions include the bcl-1 oncogene in B-cell prolymphocytic leukemia, the tcl-1 oncogene in T-cell CLL, the Hu-ets-1 and Hu-ets-2 oncogenes in small cell lymphocytic lymphoma and c-myc in a Sezary cell leukemia cell/line. Overall, it appears that oncogene abnormalities are less common in CLL than in other leukemias. The reason for it is uncertain and may relate to the relatively few cases evaluated. Alternatively, novel mechanisms of oncogene involvement or gene other than oncogenes may be important in the etiology or pathogenesis of CLL.     

Oncogenes and tumor progression

Although tumors are often characterized as being the result of uncontrolled proliferation, clinically the morbidity from cancer results from its ability to invade and metastasize and to become resistance to our current therapeutic modalities such as chemotherapy and radiation. The study of oncogenes has largely stressed their ability to alter cell growth, but in fact they also influence these crucial features of tumor progression. In this review, we will summarize the data from our laboratory that indicated that the ras oncogene can induce metastasis as well as tumorigenicity and that the ras oncogene can also influence the development of radiation resistance. We have found that these changes in cells are sometimes accompanied by characteristic non-random chromosomal alterations in the transformed cells and will speculate that these accompanying chromosomal changes also may contribute to the features of tumor progression.     

Oncogenes and thyroid tumors

Papillary thyroid carcinomas are characterized in 70% of cases by the presence of either a RET/PTC rearrangement, or an activating point mutation of RAS or BRAF genes that induce a constitutive activation of the MAP kinase pathway. Follicular carcinomas are characterized by the presence of a RAS mutation or of a PAX8-PPARgamma rearrangement. Inactivating mutations of the p53 gene are found only in anaplastic thyroid carcinomas.     

Oncogenes and metastatic progression

It is now established that ras oncogenes can induce metastatic characteristics in primary diploid fibroblasts, nonsenescing fibroblasts and nonmetastasizing tumors. The issue of whether ras is directly involved in maintaining the metastatic phenotype through the expression and action of its gene product has been examined by analyzing the relationship to ras expression and to the production of the p21 ras-GTP complex, which is thought to mediate ras-transforming activity. While these expression and mutation studies support the idea that p21 ras directly regulates metastasis formation, it is also evident that there are many examples of human and murine cancers which show no differences in ras expression in primary and metastatic tumor cells. This may be partially explained by the ability of protein kinase-encoding oncogenes to also induce metastatic potential. In addition, the ability of ras to induce metastasis may be dependent on the regulation of its activity by other genes. Furthermore, transformation does not occur as an isolated genetic event, but is rather the result of interaction of two or more oncogenes. We suggest that the nature of these gene interactions will ultimately determine whether a cell is a benign transformant or a malignant and metastatic cancer.     

Oncogenes and tumor promotion

We have studied the effects of 2 hepatic promoters: an exogenous one:phenobarbital, and an endogenous one biliverdin (a bile pigment) on the expression of 3 oncogenes c-Ki-ras, c-fos and c-myc involved in growth process, differentiation and tumorigenesis for the liver. This work was done: 1) in vitro using epithelial liver cell strains originated from 10-day old rats; 2) in vivo using regenerating liver after partial hepatectomy, as well as preneoplastic nodules obtained by the Solt and Farber procedure. In all cases we have shown an important overexpression of the oncogenes.     

Oncogenes in melanoma

Transformation of normal melanocytes into melanoma cells is accomplished by the activation of growth stimulatory pathways, typically leading to cellular proliferation, and the inactivation of apoptotic and tumor suppressor pathways. Small molecule inhibitors of proteins in the growth stimulatory pathways are under active investigation, and their application to melanoma patients would represent a new treatment strategy to inhibit cell proliferation or induce cell death. We provide a general overview of the mechanisms of oncogene activation and the functions of oncogenes. Lastly, we review oncogenic events in melanoma.     

Oncogenes in human leukemias

Eukaryotic cells contain a family of genes termed cellular oncogenes or proto-oncogenes thought to regulate normal cell growth and development. In some abnormal circumstances, such as following transduction by retroviruses, activation of these genes causes leukemias in animals. Possible mechanisms of activation of cellular oncogenes include: point mutation, deletion, or insertion; amplification; activation by internal rearrangement, chromosomal translocation, or promoter insertion; recombinatorial events resulting in the formation of novel chimeric genes; among others. In this review, we consider data implicating activation of cellular oncogenes in the pathogenesis of leukemia in humans. We discuss possible mechanisms whereby oncogene activation may induce leukemias, as well as potential diagnostic and therapeutic implications.     

Oncogenes and anti-oncogenes in breast cancer

Recent developments in molecular oncology have permitted the definition of alterations in proto-oncogenes (ras, myc, neu and hst/int.2) and anti-oncogenes (Rb.1) in human breast carcinomas. Detection of these abnormalities could be of prognostic interest. However, this remains controversial.     

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Oncogenes and Oncogenesis

Molecular biologic studies of Kaposi's sarcoma-associated herpesvirus(KSHV) have identified a number of potential viral oncogenesthat may contribute to KSHV-related neoplasia including a D-typecyclin, an IL-6-like cytokine, and a novel member of the interferonregulatory factor family. KSHV is functionally related to otherDNA tumor viruses by encoding specific proteins to inhibit pRb,pro-apoptotic, and interferon-signaling tumor suppressor pathways.The virus appears to employ molecular piracy of cellular regulatorygenes as a mechanism to avoid cellular antiviral responses.The transparency of the KSHV genome allows ready identificationof the cellular regulatory pathways which may be involved intransformation by KSHV. This provides strong support to thenotion that some tumor suppressor pathways serve the dual functionof being antiviral pathways to induce cell cycle arrest, apoptosis,and enhanced cell-mediated immunity in response to virus infection.Neoplasia may result from specific viral strategies to overcomethese host defense pathways.     

Oncogenes and oncoproteins as tumor markers.

A major problem in the management of patients with cancer is the lack of specific tumor markers for the early detection, the accurate prediction of biological behavior and for accurate assessment of prognosis. A new and exciting answer to this problem may now become available following the discovery of specific genes associated with malignancy. The role of such genes and their products are now being identified and their role in cancer is under intense investigation. On a clinical level, these genes and their products may allow us to improve our understanding of disease etiology and provide more precise diagnostic, prognostic and therapeutic characterization of individual tumors. This paper discusses the possibilities of using the altered expression of oncogenes and tumor suppressor genes and their products in neoplastic tissues as markers for the diagnosis and prognosis of malignant disease. These data support the view that detailed analysis of such gene expression has the potential to predict a tumor's behavior as well as the response to different treatment modalities.