Human T-cell leukemia virus type I (HTLV-I) infects more than 25 million people world-wide. A significant percentage of infected individuals develop adult T-cell leukemia/lymphoma (ATLL) or HTLV-I-associated myelopathy (HAM/TSP). HTLV-I-associated diseases are invariably fatal with limited therapeutic options and a life expectancy of 4-6 months for acute ATL and 10 months for the lymphoma type. Projected 4-year survival rates for acute- and lymphoma-type ATL stand at 5 and 5.7%, respectively. HTLV-I is the only known transforming human retrovirus;yet the mechanisms by which the virus transforms human T-cells are still poorly understood. The genomic instability caused by the oncoprotein Tax is thought to play an important role in ATL development. Tax has been shown to constitutively activate NF-kB and stimulate cell proliferation. In addition, Tax prematurely activates the anaphase promoting complex, inhibits nucleotide excision repair and represses topoisomerase I and beta-polymerase. This project will elucidate the mechanisms employed by Tax to increase genetic instability in pre-tumoral cells and the cellular genes involved in the adaptation/tolerance of DNA damage and transformation.

Public Health Relevance

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus and the etiological agent of adult T-cell leukemia (ATL), an aggressive and fatal disease. Approximately 5% of HTLV-1-infected individuals will develop ATL after a long latency of 20-30 years. Therefore, it can be inferred that, in addition to HTLV-I expression, multiple cumulative genetic and epigenetic alterations in the host genome may be required for ATL. This project will elucidate the mechanism by which HTLV-1 Tax induces genetic instability and transitions from pre-tumoral to the transformed state and may lead to new treatment strategies for human cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA106258-10
Application #
8676677
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kansas
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Chaib-Mezrag, Hassiba; Lemaçon, Delphine; Fontaine, Hélène et al. (2014) Tax impairs DNA replication forks and increases DNA breaks in specific oncogenic genome regions. Mol Cancer 13:205
Bellon, Marcia; Ko, Nga Ling; Lee, Min-Jung et al. (2013) Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation. Blood 121:5045-54
Yao, Yuan; Bellon, Marcia; Shelton, Shary N et al. (2012) Tumor suppressors p53, p63TAýý, p63TAy, p73ýý, and p73ýý use distinct pathways to repress telomerase expression. J Biol Chem 287:20737-47
Baydoun, Hicham H; Pancewicz, Joanna; Nicot, Christophe (2011) Human T-lymphotropic type 1 virus p30 inhibits homologous recombination and favors unfaithful DNA repair. Blood 117:5897-906
El Hajj, Hiba; El-Sabban, Marwan; Hasegawa, Hideki et al. (2010) Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia. J Exp Med 207:2785-92
Bellon, Marcia; Baydoun, Hicham H; Yao, Yuan et al. (2010) HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes. Blood 115:2441-8
Pancewicz, Joanna; Taylor, John M; Datta, Abhik et al. (2010) Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia. Proc Natl Acad Sci U S A 107:16619-24
Taylor, J M; Brown, M; Nejmeddine, M et al. (2009) Novel role for interleukin-2 receptor-Jak signaling in retrovirus transmission. J Virol 83:11467-76
Bellon, Marcia; Lepelletier, Yves; Hermine, Olivier et al. (2009) Deregulation of microRNA involved in hematopoiesis and the immune response in HTLV-I adult T-cell leukemia. Blood 113:4914-7
Taylor, John M; Nicot, Christophe (2008) HTLV-1 and apoptosis: role in cellular transformation and recent advances in therapeutic approaches. Apoptosis 13:733-47

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