MERIT Award Recipient: Riccardo Dalla-Favera, M.D.
Grant Number: R37CA037295
Award Approved: June 2002
Institution: Columbia University
Literature Search in PubMed
AIDS Associated Lymphoproliferative Disorders
The development of tumors of the lymphoid system, mainly B lymphocyte-derived non-Hodgkin lymphoma (NHL), represents one of the most serious aspects of AIDS, and its frequency is increasing among HIV-infected individuals. AIDS-associated non-Hodgkin lymphoma (AIDS-NHL) is a heterogeneous group of malignancies derived from germinal center B cells, and includes Burkitt lymphoma, diffuse large cell lymphoma and primary effusion lymphoma. During the last fifteen years, Dr. Dalla-Favera and co-workers have contributed important information on the mechanisms leading to NHL-development by identifying the genes that are specifically altered in AIDS-NHL cells. In particular they have identified the oncogenes that are involved in NHL-specific chromosomal translocations, the genetic hallmark of these tumors.
More recently, the Dalla-Favera laboratory has discovered a novel mechanism, called aberrant somatic hypermutation, which may be responsible for extensive genetic damage in NHL. They have found that the somatic hypermutation mechanism, which normally targets the immunoglobulin genes in B cells, functions aberrantly in greater than 50 percent of B cell diffuse large cell lymphoma. As a consequence, multiple genes, including several proto-oncogenes, are hypermutated in these cells, leading to their deregulated expression and/or to the production of mutant oncogenic proteins.
Dr. Dalla-Favera and co-workers will study the role of somatic hypermutation in AIDS-NHL by identifying which genes are altered in these tumors, determining the functional consequences of these alterations, and testing their effects in transgenic mouse models. In addition, this research group will exploit the power of gene expression profiling technology to analyze in detail the phenotype of AIDS-NHL subtypes, their possible further heterogeneity, and their relationship to normal B cell subpopulations by gene expression profiling.