Abstract

The current proposal is for continuation of our studies with two model systems for HTLV-1 infection, an infectious molecular clone and Tax transgenic mice. These studies focus on Tax, which appears to e the primary oncogenic determinant of HTLV-1.
The aims are: 1) To assess the mechanism of action of Tax in lymphocyte immortalization by the infectious molecular clone-We will analyze Tax mutation defective in transcriptional transactivation through CREB or NF kappaB to determine the requirement for immortalization of human lymphocytes in culture and HTLV-1 replication in rabbits. We will determine if effects of Tax on immortalization can be separated from effects on virus replication. 2) To assess the mechanism of action of Tax induction of lymphoproliferative disease in transgenic mice-We will assess the spectrum of lymphoid malignancies in Tax transgenic mice in TCR transgenic mice inoculated with ovalbumin, recognized by the TCR. We will assess the role of inactivation will be assessed in Tax transgenic mice by sequence analysis of mutated p53 alleles and by analyzing the lymphoproliferative disease in Tax transgenic, p53 -/- mice. These studies utilize 2 unique model systems to define the leukemogenic pathway mediated by HTLV-1.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063417-06
Application #
6489265
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1995-09-28
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
6
Fiscal Year
2002
Total Cost
$326,297
Indirect Cost

  Institution

Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Cherian, Mathew A; Olson, Sydney; Sundaramoorthi, Hemalatha et al. (2018) An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia. J Biol Chem 293:6844-6858
Ratner, L; Rauch, D; Abel, H et al. (2016) Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell leukemia lymphoma. Blood Cancer J 6:e408
Yeh, Chien-Hung; Bai, Xue Tao; Moles, Ramona et al. (2016) Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia. Mol Cancer 15:15
Panfil, Amanda R; Martinez, Michael P; Ratner, Lee et al. (2016) Human T-cell leukemia virus-associated malignancy. Curr Opin Virol 20:40-46
Murphy, Jane; Hall, William W; Ratner, Lee et al. (2016) Novel interactions between the HTLV antisense proteins HBZ and APH-2 and the NFAR protein family: Implications for the HTLV lifecycles. Virology 494:129-42
Baydoun, Hicham H; Cherian, Mathew A; Green, Patrick et al. (2015) Inducible nitric oxide synthase mediates DNA double strand breaks in Human T-Cell Leukemia Virus Type 1-induced leukemia/lymphoma. Retrovirology 12:71
Bangham, Charles R M; Ratner, Lee (2015) How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)? Curr Opin Virol 14:93-100
Romeo, Megan M; Ko, Bookyung; Kim, Janice et al. (2015) Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30(II) accessory protein and the induction of oncogenic cellular transformation by p30(II)/c-MYC. Virology 476:271-88
Cherian, Mathew A; Baydoun, Hicham H; Al-Saleem, Jacob et al. (2015) Akt Pathway Activation by Human T-cell Leukemia Virus Type 1 Tax Oncoprotein. J Biol Chem 290:26270-81
Pujari, Rajeshree; Hunte, Richard; Thomas, Remy et al. (2015) Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-?B inhibitor A20 and constitutive NF-?B signaling. PLoS Pathog 11:e1004721

Showing the most recent 10 out of 47 publications