Project 2: Early crosstalk between HTLV-1 infected T cells and bone microenvironment

Washington University, Saint Louis MO

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Abstract

PROJECT SUMMARY/ABSTRACT - PROJECT 2: Early crosstalk between HTLV-1 infected T cells and bone microenvironment Adult T cell leukemia/lymphoma (ATLL), a malignancy of HTLV-1 infected T cells, stands out from other acute leukemias in its frequent association with hypercalcemia and propensity to form localized lymphomatous osteolytic lesions. Osteoclasts are directly responsible for the degradation of bone that releases calcium. In the previous funding period, we demonstrated that patient derived ATLL cells (ATLL-PDX) and a subset of HTLV- infected T cell lines release small extracellular vesicles (sEV) with powerful osteoclastogenic effects in vitro and in vivo. We have found that the proteome of osteolytic sEV is enriched for metabolic pathways; in concert, the transcriptional signature of osteoclasts exposed to these sEV reflect a metabolic shift, demonstrating enhanced glycolysis and hypoxia, features of a tumorigenic microenvironment. We hypothesize that crosstalk between HTLV+T and osteoclasts provides a tumorigenic microenvironment impacting HTLV+T cell fate. Previous work, including our own, has focused primarily on the ability of transformed ATLL cells to enhance the formation and activation of osteoclasts. This proposal’s focus on HTLV-1 infected T cells prior to transformation and the feedback on osteoclasts and other cells in bone, is novel. Aim 1: Define impact of the bone microenvironment on HTLV-1 infected T cells via Notch and TGFβ. In this aim, we examine the signals from bone, resulting from crosstalk with HTLV+T, that impact the fate of HTLV+T cells. To do this, we will profile gene expression and the epigenetic state of HTLV+T cells residing in bone from our mouse model, compared to extraskeletal site. Aim 2: Define the role of osteoclasts in remodeling of the bone microenvironment by HTLV-1 infected T cells and their sEV. We will implant HTLV+T or their sEV into bones of mice, with or without osteoclast blockade, and perform detailed analysis of bone tissue by morphological and molecular analysis. We will also determine the role of serum amyloid A, released by OC, and mir155 and mir21 present in osteolytic sEV. The successful completion of this project will provide detailed information about cellular and molecular interactions that may be therapeutically targeted to reduce the transition to ATLL or used to identify risks for progression.