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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Read-Connole, Elizabeth Lee
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University of Kansas
Schools of Medicine
Kansas City
United States
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Bai, Xue Tao; Yeh, Chien-Hung; Nicot, Christophe (2017) NOTCH1 Activation Depletes the Pool of Side Population Stem Cells in ATL. J Cancer Sci 4:
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
Moles, R; Bai, X T; Chaib-Mezrag, H et al. (2016) WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells. J Hematol Oncol 9:121
Bellon, Marcia; Lu, Ling; Nicot, Christophe (2016) Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia. Blood 127:2439-50
Yeh, Chien-Hung; Moles, Ramona; Nicot, Christophe (2016) Clinical significance of microRNAs in chronic and acute human leukemia. Mol Cancer 15:37
Nicot, Christophe (2015) HTLV-I Tax-Mediated Inactivation of Cell Cycle Checkpoints and DNA Repair Pathways Contribute to Cellular Transformation: ""A Random Mutagenesis Model"". J Cancer Sci 2:
Bellon, Marcia; Nicot, Christophe (2015) Multiple Pathways Control the Reactivation of Telomerase in HTLV-I-Associated Leukemia. Int J Cancer Oncol 2:
Bai, Xue Tao; Moles, Ramona; Chaib-Mezrag, Hassiba et al. (2015) Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells. J Hematol Oncol 8:117
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

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