This is a proposal to utilize Tax transgenic animals to enhance our understanding of principles of molecular oncology that govern development of HTLV-1 associated neoplasia that are broadly applicable to many forms of neoplasia. Our previous studies have shown that tumors in Tax transgenic mice are resistant to the induction of apoptosis after gamma irradiation. Since Tax inactivates p53 and activates NFkB, we will examine if these findings explain the effects on apoptosis or whether another mechanism is involved.
Aim 1 how does HTLV infection affect apoptosis? 1a. Is the canonical or non-canonical NF kB pathway important for resistance to apoptosis? 1b. Which NFkB inducible genes are responsible for resistance to apoptosis 1c. Is resistance to apoptosis due to induction of FLIP, bcl-XL, A1, or IAP2 or another mechanism? 1d. is resistance to apoptosis a direct or indirect effect of Tax expression? We will further examine the role of p53, in light of the studies in Aim 1 and our previous studies that Tax transgenic p53 heterozygous mice as compared to Tax transgenic, p53 homozygous wild type mice exhibited more rapid tumor dissemination.
Aim 2. What is the contribution of loss of p53 function to HTLV tumorigenesis? 2a. Are p53 transcriptional transactivation properties disrupted in Tax transgenic mice? 2b. Is p53 mutated, deleted, or repressed with tumor dissemination? 2c. What biological differences account for altered tumor dissemination in p53 mice? One central and unanswered question is why is HTLV-1 so highly specific for transformation of lymphoid compartment cells.
Aim 3. What regulates the cell-type specificity of HTLV transformation? What is the role of IL15 in Tax transgenic animals?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063417-12
Application #
7821254
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1995-09-28
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
12
Fiscal Year
2010
Total Cost
$317,369
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
Panfil, Amanda R; Martinez, Michael P; Ratner, Lee et al. (2016) Human T-cell leukemia virus-associated malignancy. Curr Opin Virol 20:40-46
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
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
Rauch, Daniel A; Harding, John C; Ratner, Lee (2014) IL-15 deficient tax mice reveal a role for IL-1? in tumor immunity. PLoS One 9:e85028

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