Abstract

The human T-cell leukemia/lymphoma virus type 1 (HTLV-I) is a complex retrovirus. HTLV-I infection is epidemiologically associated with an aggressive and fatal T-cell type leukemia/lymphoma designated as Adult T-cell Leukemia/ Lymphoma (ATLL). HTLV-I infection is also associated with a progressive myelopathy designated Tropical Spastic Paraparesis/ HTLV-I-Associated Myelopathy (TSP/HAM) of probable immune-mediated pathogenesis. The virus is transmitted through sexual contacts, contaminated blood and from mother-to-child by breast feeding and it is estimated that 20 to 30 million people worldwide are infected with HTLV-I. The provirus genome encodes a viral transactivator, Tax, which is critical for viral replication, cellular transformation and pathogenesis. Tax stimulates transcription through CREB, NF-kappaB and SRF resulting in deregulated expression of various cellular genes. While NF-kB activation appeared important for short term IL-2-dependent proliferation, unexpectedly neither the activation of CREB/ATF nor NF-kB were sufficient to support long term T-cell immortalization by Tax and a novel domain was identified. The goals of this proposal are to understand the sequence of events that take place during Tax-mediated human T-cell immortalization (IL-2-dependent) and transformation (IL-2-independent). Based upon our data three aims are proposed:
Aim l. Characterize cellular pathways involved in short term and long term Tax-mediated IL-2 dependent T-cell proliferation and immortalization and identify the cellular genes involved to bypass each crisis.
Aim 2. Study of Tax's effect on hTERT promoter stimulation and telomerase activity.
Aim 3. Identify cellular or viral genes involved together with Tax in the switch from IL-2-dependent to IL-2-independent T-cell transformation. We believe that a better understanding on mechanisms employed by Tax will provide basic information on human T-cell transformation processes and may reveal new therapeutic targets for the treatment of T-cell leukemia/lymphoma.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA106258-06
Application #
7532790
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2004-12-15
Project End
2011-06-30
Budget Start
2008-12-01
Budget End
2011-06-30
Support Year
6
Fiscal Year
2009
Total Cost
$219,529
Indirect Cost

  Institution

Name
University of Kansas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160

  Publications

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:
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
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
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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