Abstract 403: Deletion of HBZ alters lymphomagenesis in HTLV-1 infected humanized SCID mice

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of Adult T-cell Leukemia (ATL), an aggressive, mature CD4+/CD25+ T-cell malignancy. The early molecular events induced by HTLV-1 infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+ HPCs). Humanized NOD/SCID (HU-SCID) mice generated by injection with HTLV-1-infected CD34+ HPCs demonstrate persistent infection and reproducibly develop CD4+ T-cell lymphomas (∼80%) with clinical characteristics associated with ATL. The HTLV-1 bZIP protein (HBZ) is consistently expressed in all ATL cells and has been implicated in the maintenance of leukemogenesis. HBZ has previously been demonstrated to modulate Tax activity and to interact with the cellular factors CREB, Jun and p53. Transduction of HBZ into CD34+ HP/HSCs using a lentivirus vector suppresses clonogenic colony formation in vitro. Moreover, infection of CD34+ HP/HSCs with an infectious proviral clone lacking functional HBZ (HTLV-1ΔHBZ) results in elevated clonogenic colony formation in vitro, suggesting that HBZ suppresses hematopoiesis. To establish the role of HBZ in HTLV-1 replication and leukemogenesis in vivo, HU-SCID mice were infected with an infectious proviral clone lacking functional HBZ (HTLV-1ΔHBZ). HTLV-1ΔHBZ-infected HU-SCID mice developed lymphoproliferations that were phenotypically characterized as a mixture of immature lymphoid progenitors (CD90+) and mature B-cells (CD19+) starting at ∼10 weeks post-reconstitution, in contrast to wild-type HTLV-1 infection. Lymphoproliferations induced by HTLV-1ΔHBZ successfully engraft and expand in naive NOD/SCID mice when injected into the peritoneal cavity and leukemic cells and lymphoma cells express HTLV-1 gp46env and p19gag. FACS-purified CD90+CD19− HTLV-1ΔHBZ infected cells also successfully engraft in naive NOD/SCID mice and mature into CD19+ cells suggesting that these cells may be leukemic progenitors with the capability of maturing in vivo. In addition, a majority of HTLV-1ΔHBZ-infected HU-SCID mice also develop a progressive, flaccid hind limb paralysis with features similar to the neurological disorder, HAM/TSP. These results suggest that HBZ is dispensable for HTLV-1 replication and modulates lymphomagenesis in the HU-SCID model. The humanized SCID mouse provides a novel in vivo platform for analysis of the role of HTLV-1 genes in viral replication and pathogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 403.