Genetic mutations promoting autonomous B cell proliferation

Abstract

The multi-step nature of neoplastic transformation is relatively well accepted, although the minimum number of genetic perturbations required for the acquisition of a malignant phenotype has not previously been clearly defined. Using retroviral gene transfer, cells harbouring mutated Trp53 in conjunction with overexpressed MYC have been demonstrated to predispose to B cell lymphoma development in mice. We localised retroviral insertion sites in 24 such lymphomas. Many of these integration sites were similar to those identified in other murine models of malignancy. Oncogenes, proto-oncogenes and B cell regulators were over-represented within these common integration sites. cDNAs encoding a selection of genes adjacent to the retroviral insertion sites were engineered into separate retroviral expression vectors under the control of the retroviral enhancer and promoter region to determine if they facilitated B cell transformation. Double transduction of Myb and MYC suggested that the overexpression of Myb and MYC in Trp53 mutated cells is sufficient for autonomous B cell growth in vitro. This novel finding improves understanding of the genetic basis of B cell transformation, and further research based on these findings may provide insights into the pathogenesis and cellular pathways implicated in the development of B cell lymphoma. The recognition that Myb and MYC were the most notable oncogenes implicated in the induction of B-cell lymphoma increases the need and perhaps opportunity to consider experimental strategies that inhibit Myb and/or MYC function and thus may offer new therapeutic approaches to treating such malignancies. Show more