# Project 2: Effect of HTLV-1 Viral Oncogenes on the Bone Microenvironment during tumor growth and progression in ATL

> **NIH NIH P01** · OHIO STATE UNIVERSITY · 2020 · $376,735

## Abstract

PROJECT SUMMARY – PROJECT 2
Adult T-cell leukemia/lymphoma (ATL) develops in a subset of people infected with HTLV-1 and is an aggressive
T-cell malignancy. ATL’s unique relationship to bone (long latency in the marrow, bone invasion, osteolytic
lesions, and hypercalcemia) makes it an ideal model to dissect the critical factors that support tumor development
and progression in bone. Thus, our work on ATL will likely shed light on other late recurring and bone-tropic
tumors like multiple myeloma, breast, and prostate cancer. Using transgenic mice, we showed that the HTLV-1
tax viral oncogene can mediate both ATL development as well as osteolytic bone destruction through effects on
bone-resorbing osteoclasts (OCs). However, Tax expression is downregulated in ~70% of human ATL, despite
ongoing bone involvement and bone loss, suggesting that another viral factor is important. Recently, we found
that HBZ, a second HTLV-1 oncogene, can also lead to lymphoproliferative disease and pathologic bone loss
when expressed transgenically or in a humanized mouse model of HTLV-1 infection. RANKL plays an important
role in this process, but is not a direct target of HBZ. We and others find that HBZ upregulates the expression of
Wnt5a and heparanase (HPSE), tumor-derived paracrine factors that modulate the tumor microenvironment in
bone and are upregulated in patient ATL cells. Wnt5a activates noncanonical Wnt signaling via Ror2 and has
both osteoblast-inhibiting and OC-stimulating activities, including increasing RANKL expression. HPSE
enzymatically cleaves heparan sulfate, thereby altering cell surfaces and extracellular matrix, increasing
bioavailability of growth factors and cytokines including RANKL and likely Wnt5a. We hypothesize that hbz
expression in transformed ATL cells reprograms the bone microenvironment via increasing Wnt5a and
Heparanase expression, and thereby affects tumor progression and bone loss.
Our plan for evaluating this hypothesis relies integrally on the in vivo models that were developed during the
previous funding period, including new patient-derived xenograft (PDX) models that cause systemic bone loss
in mice following intraperitoneal (IP) implantation and newly characterized local bone effects of established ATL
cell lines following implantation into bone (with intratibial injection; IT). We will make extensive use of viral vectors
to manipulate Wnt5a and HPSE in these ATL and PDX lines, primarily with CRISPR/Cas9, taking advantage of
the expertise of Dr. Yoder (Vector Core 1). In collaboration with Dr. Niewiesk (Animal Core 2), we have also
implemented a humanized immune system (HIS) model in which immunodeficient mice are transplanted with
human cord blood cells, and then infected with HTLV-1, modeling emergence of lymphoproliferative disease
(LPD) accompanied by systemic bone loss. This collaboration will be a key part of our experimental design.

## Key facts

- **NIH application ID:** 10023352
- **Project number:** 2P01CA100730-16A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Katherine Nelson Weilbaecher
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,735
- **Award type:** 2
- **Project period:** 2003-04-21 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023352

## Citation

> US National Institutes of Health, RePORTER application 10023352, Project 2: Effect of HTLV-1 Viral Oncogenes on the Bone Microenvironment during tumor growth and progression in ATL (2P01CA100730-16A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10023352. Licensed CC0.

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