Abelson Virus Transformation
A Model System to Study Human Cancer Development

Although cancer is a diverse group of diseases, virtually all cancers are multi-step in nature and involve aberrant growth stimulation, inappropriate suppression of apoptosis and differentiation arrest. Understanding the complex interplay of signals from oncoproteins and tumor suppressor proteins that determine the fate of individual cells and ultimately their host holds the key to unraveling mechanisms that govern the cancer development and will ultimately lead to improved therapeutic interventions. The Rosenberg lab uses the highly oncogenic Abelson murine leukemia virus (Ab-MLV) to attack fundamental questions relating to the mechanisms by which cancer develops. Infection of susceptible mice with this virus induces pre-B cell lymphoma, a tumor of developing B lymphocytes; infection of bone marrow cells in vitro induces transformation of a similar cell type. The high frequency with which Ab-MLV induces tumors and the simple genetic organization of the virus provides an easily manipulable system to understand the mechanisms of tumor induction. In addition, because human chronic myelogenous leukemia and some acute lymphocytic leukemias are caused by the related BCR/ABL protein, results obtained in this model can be directly relevant to human disease.

Ab-MLV is a replication defective retrovirus that encodes a single protein tyrosine kinase called the v-Abl protein. When v-Abl protein is expressed in cells, signals generated by the kinase activate the Ras, PI-3 kinase, and JAK-STAT signaling pathways. Signals transmitted by these and perhaps other pathways lead to altered gene expression and stimulation of cell growth. Despite the clear importance of these signals, the intermediates involved in the pathways and a thorough understanding of which events are critical for transformation is poorly understood. We are using a combination of biologically-derived and genetically engineered mutants to dissect these pathways. Because transformation involves suppression of apoptosis, stimulation of growth and suppression of differentiation, we are particularly interested in understanding if these different events are orchestrated by a common pathway or if they involve distinct or perhaps partially overlapping cascades. This information may help guide the design of therapeutic agents that could target specific aspects of the tumorigenic process.

A second important part of the transformation process involves cellular events that occur in response to inappropriate oncogenic signals. Disabling the p53 tumor suppressor pathway is a critical event in many cancers and the majority of lymphocytes fully transformed by Ab-MLV display this property. Many transformants contain mutated p53 alleles and others have down-modulated the p19Arf protein, an important activator of p53. We are using the Abelson virus system to understand the ways in which this tumor suppressor pathway senses inappropriate growth and also examining the way underlying defects in DNA repair alter the outcome of the transformation process. Because the p53 pathway is of critical importance in many cancers, the results we obtain are likely to advance our understanding of the ways in which this tumor suppressor functions.

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