HTLV-1 is the etiological agent of adult T-cell leukemia lymphoma (ATLL). ATLL cells are characterized by constitutive NF?B activation, a key feature of other lymphomas, myeloma, and solid tumors. The Tax oncoprotein is the key viral determinant for NF?B activation. Our previous studies showed that the classical and especially, the alternative NF?B pathways were critical in conferring resistance to apoptosis. Our primary hypothesis is that Tax activation of NF?B is critical for tumorigenesis, particularly the alternative (alt) NF?B pathway. The current study will use innovative, physiological lymphoma models to define the role in tumorigenesis of each NF?B pathway and identify the key regulators of the NF?B pathway.
Aim 1. Aim 1. To assess the role of alt NF?B activity in Tax-mediated transformation A new humanized mouse model is used for HTLV-1 infection and lymphoma development. We will use viral variants expressing Tax mutants with defects in activating the alternative NF?B pathway or both NF?B pathways, in order to define their role in disease pathogenesis. A novel high-throughput viral integration assay is used to monitor clonality of infected cells in these experiments.
Aim 2. To identify and characterize Tax interactive proteins that mediate alt NF?B activation We will identify Tax interactive proteins that mediate alt NF?B pathway activation. Proteins that interact with wild type but not mutant Tax will then be characterized using shRNAs to assess their effect on Tax induced cleavage of alt NF?B precursor protein, p100, as well as effects on proliferation and apoptosis of HTLV-1 transformed cells in culture and immunodeficient mice. It is expected that the information these physiologically relevant mouse models will identify key target genes that may be inhibited in therapeutic trials of ATLL or other lymphomas.

Public Health Relevance

HTLV-1 causes an aggressive form of leukemia/lymphoma. The Tax protein is critical for tumor initiation. Tax activation of gene expression through the nuclear kappa B (NFkB) pathway is responsible for the ability of these tumor cells to avoid cell death. The current project examines the role of the

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA100730-11A1
Application #
8742042
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2014-09-23
Project End
2019-08-31
Budget Start
2014-09-23
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$419,534
Indirect Cost
$110,473
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
M Parrula, M Cecilia; Fernandez, Soledad A; Landes, Kristina et al. (2014) Success of measles virotherapy in ATL depends on type I interferon secretion and responsiveness. Virus Res 189:206-13
Dissinger, Nathan; Shkriabai, Nikoloz; Hess, Sonja et al. (2014) Identification and characterization of HTLV-1 HBZ post-translational modifications. PLoS One 9:e112762
Soodgupta, Deepti; Hurchla, Michelle A; Jiang, Majiong et al. (2013) Very late antigen-4 (*(4)*(1) Integrin) targeted PET imaging of multiple myeloma. PLoS One 8:e55841
Yang, Chang; Davis, Jennifer L; Zeng, Rong et al. (2013) Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast activation. Cancer Discov 3:212-23
Kannian, Priya; Fernandez, Soledad; Jones, Kathryn S et al. (2013) Human T lymphotropic virus type 1 SU residue 195 plays a role in determining the preferential CD4+ T cell immortalization/transformation tropism. J Virol 87:9344-52
Hurchla, M A; Garcia-Gomez, A; Hornick, M C et al. (2013) The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia 27:430-40
Jacob, Aishwarya G; O'Brien, Dennis; Singh, Ravi K et al. (2013) Stress-induced isoforms of MDM2 and MDM4 correlate with high-grade disease and an altered splicing network in pediatric rhabdomyosarcoma. Neoplasia 15:1049-63
Sharma, Amit; Larue, Ross C; Plumb, Matthew R et al. (2013) BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proc Natl Acad Sci U S A 110:12036-41
Kessl, Jacques J; Jena, Nivedita; Koh, Yasuhiro et al. (2012) Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 287:16801-11
Heller, Emanuela; Hurchla, Michelle A; Xiang, Jingyu et al. (2012) Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Res 72:897-907

Showing the most recent 10 out of 106 publications