Adult T Cell Leukemia/Lymphoma Development in HTLV-1-Infected Humanized SCID Mice.

Abstract 1425

Poster Board I-448

Human T-lymphotropic virus type-1 (HTLV-1) is the first human retrovirus linked to cancer and is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4⁺ T cell malignancy. The molecular and genetic factors induced by HTLV-1 that initiate ATLL remain unclear, in part, due to the lack of an animal model which recapitulates leukemogenic events. In particular, early target cell infection and transformation events have not been identified or defined. Herein, we have created humanized NOD/SCID (HU-NOD/SCID) mice by inoculation of NOD/SCID mice with CD34⁺ hematopoietic progenitor and stem cells (CD34⁺ HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCID mice consistently developed CD4⁺ T cell lymphomas with characteristics similar to ATLL. Elevated proliferation of infected human stem cells (CD34⁺CD38⁻) in the bone marrow was observed in mice developing malignancies. Furthermore, examination of CD34⁺ HP/HSCs from HTLV-1-infected patients revealed proviral integrations suggesting a role of human bone marrow-derived stem cells in leukemogenesis. NOD/SCID mice reconstituted with CD34⁺ HP/HSCs transduced with a lentivirus vector (LV) expressing the HTLV-1 oncoprotein (Tax1) also developed CD4⁺ lymphomas. The recapitulation of a CD4⁺ T cell lymphoma in HTLV-1- and Tax1-HU-NOD/SCID mice suggest that hematopoietic stem cells serve as a viral reservoir in vivo and provide a cellular target for cell transformation in humans. This animal model of HTLV-1 induced ATLL will provide an important tool for the identification of molecular and cellular events that control the initiation and progression of the lymphoma and potential therapeutic targets to block tumor development.