Adult T-cell leukemia/lymphoma (ATL) develops in people infected with HTLV-1 and is an aggressive malignancy of helper T-lymphocytes, associated with hypercalcemia and osteolytic bone lesions. We found that the HTLV-1 tax viral oncogene is critical to both ATL development and to osteolytic bone destruction through non-cell autonomous effects on bone resorbing osteoclasts (OC). We discovered that Tax and the newly identified viral oncogene, HTLV-1 basic leucine zipper, Hbz, can regulate the expression of paracrine factors that modulate the tumor microenvironment in bone, specifically through the expression of Hedgehog (Hh) ligands which promote bone turnover and WNT modulators (DKK1 and sclerostin) which inhibit differentiation of osteoblasts (OB). Immature OB produce higher levels of the OC promoting, RANKL, and stem cell niche homing factor, SDF1. We hypothesize that Tax and Hbz expression in HTLV-1-infected T cells and transformed ATL cells reprogram the bone microenvironment and are essential for both HTLV-1-induced cellular transformation and progression. We propose the following aims:
Aim 1 : Determine how Hbz and Tax modulate the bone microenvironment during HTLV-1 infection, transformation, and leukemic progression.
Aim 2 : Characterize Tax/Hbz-dependence on tumor-bone cell interactions mediated by the Hedgehog (Hh) pathway.
Aim 3 : Determine the roles of Tax and/or HBZ on WNT pathway genes that modulate the bone microenvironment during ATL development and progression. This project will involve essential collaborations and sharing of data and reagents with Projects 1 and 4 (for in vivo HBZ+ and Tax+ tumor models, Tax/Hbz mutant viruses and cells), Project 2, 4, and Core B (proteomic analyses), Project 1 and Core A (statistical and data analyses) and Core C (generation of and histologic characterization of humanized HTLV-1-HIS mice). Together with the other PPG members, our long-term goal is to identify new roles for HTLV-1 viral oncogenes in reprogramming the tumor microenvironment in bone after infection and during leukemic transformation through non-cell autonomous mechanisms leading to the rational development of new therapeutic approaches for ATL.
Adult T-cell leukemia/lymphoma (ATL), an aggressive leukemia that is associated with hypercalcemia and osteolytic bone lesions develops in HTLV-1-infected individuals. We will investigate new roles for two HTLV-1 viral oncogenes, Tax and Hbz, in reprogramming the tumor microenvironment in bone through non-cell autonomous mechanisms and will develop new therapeutic approaches for ATL, which is often refractory to standard chemotherapy.
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