Activation of the putative oncogene bcl-2 is implicated as one of the causative factors in the development of B cell lymphomas in humans. However, little is known about the role of bcl-2 in the transformation process, or its involvement in the development of other types of neoplasias. Furthermore, very little is known about how bcl-2 is involved in normal embryonic development and cellular differentiation. The goal of this project is to elucidate the role of the bcl-2 gene product in neoplastic and normal cellular development. The starting point of our investigation will be our observation that overexpression of the human bcl- 2 gene is an avian retroviral vector (RCASbcl-2) results in the development of neoplasia involving a variety of tissues and multiple cell lineages in the chicken. The recently developed replication competent RCAS vectors permit expression of the bcl-2 gene in most tissues and under transcriptional control of a variety of viral promoters of different strengths. This is the first system in which the bcl-2 gene has been shown to cause neoplastic transformation, apparently, independent of the involvement of other known oncogene(s). Our first goal will be to characterize the different neoplasias with emphasis on the state of differentiation of the transformed cell, as well as that of the initial target cell of transformation. We will also examine the involvement of other oncogenes, in addition to bcl-2, that may be activated by proviral integration and be involved in the transformation process. In addition to the effect of constitutive bcl-2 deregulation on neoplastic transformation we will also examine its effect on hematopoietic cell development and function. Beginning with our observation that overexpression of bcl-2 blocks apoptosis in immature B cells in the bursa of Fabricius, we will proceed to determine what effect bcl-2 deregulation has on the differentiation and maturation of B cells as well as other lineages of hematopoietic cells. We will also analyze the effect that deregulation of bcl-2 expression has on the development and progression of B cell lymphomas that are initiated by proviral insertion in the c-myc locus. In addition to analyzing the effects of aberrant expression of bcl-2 we will examine the role of bcl-2 in normal embryonic development particularly in the differentiation and maturation of the lymphoid system. The avian system is well suited for studies of ontogeny because of the accessibility of the embryo to manipulation and particularly for the analysis of hematopoietic cell development because of the compartmentalization of the sites of B cell and T cell development in discrete organs. We will begin the studies by using the currently available human bcl-2 probes, which we have shown to cross-hybridize with the avian homologue under stringent conditions. Since the avian bcl-2 homologue has never been shown to be involved in avian lymphomagenesis in the chicken, we will clone and characterize the chicken bcl-2 gene, compare it with the human and chicken sequences and determine if the overexpressed chicken gene can also induce tumor formation.
NIH ExPorter
NIH ExPorter