Pax5 is a key regulator of B-cell differentiation, necessary for commitment to the B-lymphoid lineage. Its absence allows pro-B-cells to readily adopt other fates. Conversely, failure to silence Pax5 in pre-B-cells is thought to contribute to neoplastic transformation. For example, Pax5 is over-expressed in lymphoplasma-cytic lymphomas due to a chromosomal translocation juxtaposing pax5 and IgH loci. In other types of non-Hodgkin disease (diffuse large cell and Burkitt lymphomas), Pax5 is often co-expressed along with Myc, a confirmed oncogene. However, the role of Pax5 as an oncogene in its own right is yet to be established. To this end, a model system has been developed wherein p53-null bone marrow cells are transduced in vivo with retroviruses expressing Myc. In syngeneic hosts, these cells give rise to aggressive, Pax5-positive B-cell lymphomas. However, some cell lines derived therefrom spontaneously silence Pax5 and convert to a myeloid phenotype, with frequent loss of tumorigenicity. Thus, physiological levels of Pax5 are crucial for the B-lymphoid phenotype of Myc-induced neoplasms. Moreover, supraphysiological levels of Pax5, achieved via retroviral transduction, were found to greatly enhance Myc-induced tumor cell growth. In the current proposal, the retroviral transduction system will be used to elucidate the exact role of Pax5 in lymphomagenesis. Three important issues will be addressed. 1. The role of Pax5 in restricting Myc-induced hematopoietic neoplasms to B-lymphomas. The hypothesis is that Myc-transformed cells are multipotent. To remain committed to the lymphoid lineage and thwart myeloid differentiation, they require Pax5 which serves as an antagonist of the pro-myeloid transcription factor PU.1. 2. The transforming potential of Pax5 in bone marrow cells. The hypothesis is that at least in the absence of p53, Pax5 can initiate neoplastic growth and supplant Myc in tumor sustenance. 3. The consequences of Pax5 silencing for B-lymphomagenesis. The hypothesis is that inactivation of Pax5 in neoplastic pre-B cells will result in loss or attenuation of tumorigenicity. These experimental results may identify Pax5 as a valid target for gene-specific therapeutic interventions that would benefit patients with a variety of B-cell lymphomas.
Showing the most recent 10 out of 19 publications
