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Project 3

Project 3

Effect of HTLV-1 viral oncogenes
on the bone microenvironment in ATL

Principal Investigator: Katherine Weilbaecher, MD, Washington University
Co-Investigator: Thomas Rosol, DVM, PhD, The Ohio State University

Project 4 lab

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 specific 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.

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.

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