Retrovirus Models of Cancer

Washington University, Saint Louis MO

Investigators

Linked publications, trials & patents

Abstract

OVERALL PROJECT SUMMARY This competitive renewal application (P01CA100730) seeks funds to continue our highly integrated studies of retrovirus models to elucidate cellular mechanisms of lymphocyte transformation and associated lymphoproliferative disease. Infection of CD4+ T-cells with the human retrovirus, human T-cell leukemia virus type 1 (HTLV-1), induces their immortalization and enables those cells to accumulate genetic mutations leading to the lymphoproliferative malignancy, adult T-cell leukemia lymphoma (ATLL). The advantage of the HTLV-1 model to study leukemogenesis is the rapid induction of T-cell immortalization brought about by the viral infection. This model of leukemogenesis allows careful examination of the biologic changes and response patterns of virus infected preneoplastic cells while under the influence of cellular and viral factors that control and perhaps promote progression to cancer. In the previous funding period we made substantial advances in our understanding of: 1) how the HTLV-1 transforming gene, hbz, contributes to cell immortalization; 2) how chromatin insulator, CTCF, controls HTLV-1 gene expression and pathogenesis; 3) and how HTLV-1 infected cells contribute to bone destruction through production of extracellular vesicles; and 4) how ATLL can be targeted for anticancer therapy and HTLV-1 infection prevented by an envelope mRNA vaccine. In the next funding period, the overall theme of the Program Project is to continue our studies with the HTLV-1 lymphoproliferative disease model with a focus on discovering how key viral, cellular and microenvironmental factors work in concert to promote T-cell malignancy. We now recognize three interrelated areas of study that are major gaps in our understanding of the pathogenesis of HTLV-1-associated T-cell leukemogenesis: 1) Immune correlates of prevention and treatment with envelope and hbz vaccines; 2) The effect of HTLV-1 chromatin insulators on T- cell immortalization, reactivation from latency, and contribution to the transition to and progression of ATLL, and; 3) Bone microenvironmental factors that contribute to the survival and expansion of HTLV-1-infected T-cells and their progression to ATLL.