Expression of parathyroid hormone-related protein during immortalization of human peripheral blood mononuclear cells by HTLV-1: Implications for transformation

Murali Vp Nadella,Thomas J Rosol,Wessel P Dirksen,Michael D Lairmore,Nanda K Thudi,Soledad A Fernandez,Sherry T Shu,Kiran S Nadella,Patrick L Green

doi:10.1186/1742-4690-5-46

Abstract

BackgroundAdult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-lymphotropic virus type-1 (HTLV-1); however, additional host factors are also required for T-cell transformation and development of ATLL. The HTLV-1 Tax protein plays an important role in the transformation of T-cells although the exact mechanisms remain unclear. Parathyroid hormone-related protein (PTHrP) plays an important role in the pathogenesis of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of ATLL patients. However, PTHrP is also up-regulated in HTLV-1-carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients without hypercalcemia, indicating that PTHrP is expressed before transformation of T-cells. The expression of PTHrP and the PTH/PTHrP receptor during immortalization or transformation of lymphocytes by HTLV-1 has not been investigated.ResultsWe report that PTHrP was up-regulated during immortalization of lymphocytes from peripheral blood mononuclear cells by HTLV-1 infection in long-term co-culture assays. There was preferential utilization of the PTHrP-P2 promoter in the immortalized cells compared to the HTLV-1-transformed MT-2 cells. PTHrP expression did not correlate temporally with expression of HTLV-1 tax. HTLV-1 infection up-regulated the PTHrP receptor (PTH1R) in lymphocytes indicating a potential autocrine role for PTHrP. Furthermore, co-transfection of HTLV-1 expression plasmids and PTHrP P2/P3-promoter luciferase reporter plasmids demonstrated that HTLV-1 up-regulated PTHrP expression only mildly, indicating that other cellular factors and/or events are required for the very high PTHrP expression observed in ATLL cells. We also report that macrophage inflammatory protein-1α (MIP-1α), a cellular gene known to play an important role in the pathogenesis of HHM in ATLL patients, was highly expressed during early HTLV-1 infection indicating that, unlike PTHrP, its expression was enhanced due to activation of lymphocytes by HTLV-1 infection.ConclusionThese data demonstrate that PTHrP and its receptor are up-regulated specifically during immortalization of T-lymphocytes by HTLV-1 infection and may facilitate the transformation process.

Highlights

Adult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-lymphotropic virus type-1 (HTLV-1); additional host factors are required for T-cell transformation and development of ATLL
HTLV-1-infected PBMCs proliferate beyond six weeks To investigate the expression of Parathyroid hormone-related protein (PTHrP) early after HTLV-1 infection, we used long-term co-culture assays of PBMCs from healthy human donors with irradiated HTLV-1 producer cells (SLB-1) in the presence or absence of IL-2
Our data demonstrated that PTHrP was dramatically and up-regulated during the immortalization of PBMCs with HTLV-1 in a Tax-independent manner

Summary

Introduction

Adult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-lymphotropic virus type-1 (HTLV-1); additional host factors are required for T-cell transformation and development of ATLL. PTHrP is up-regulated in HTLV-1-carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients without hypercalcemia, indicating that PTHrP is expressed before transformation of T-cells. Human T-lymphotropic virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a variety of other disorders [1,2]. The long latency period and the relatively low proportion of HTLV-1-infected people that develop ATLL reflect the inefficiency of the virus to transform cells and the need for multiple cooperative changes in growth control mechanisms to induce leukemogenesis. The accessory genes p12, p30, p13 and HBZ contribute to establishing persistent viral infection in vivo but are not required for transformation of cells in vitro [17,18]

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