Human T-cell Leukemia Virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia, an aggressive and fatal disease characterized by a clonal expansion of virus-infected CD4+T cells. It is estimated that 20 to 30 million people worldwide are infected with HTLV-I. Overall, survival of HTLV-I-infected patients with acute leukemia treated with various chemotherapy or radiotherapy regimens is limited and median survival is 8 months. Consequently, identification of new potential therapeutic targets is greatly needed. Our studies previously demonstrated that intracellular activated Notch1 (ICN1) is constitutively activated in HTLV-I-transformed T-cells and HTLV-I-associated adult T-cell leukemia, and is essential for tumor cell growth in an in vivo mouse model. Recent data from our laboratory suggest that the viral Tax oncoprotein reduces degradation of ICN1, leading to constitutive signaling in HTLV-I-infected cells. We further found that Tax- mediated NF-kappa B2 activation was involved in constitutive ICN1 signaling. Activation of the "non-canonical" NF-kB pathway has emerged as an important pathway involved in T-cell leukemia and lymphomas. The Nfkb2 gene is frequently involved in chromosomal translocations associated with human cutaneous T-cell lymphomas. In addition, activation of NF-kappaB is essential for HTLV-I-transformed cells and inhibition of the pathway prevents tumor growth in vitro and in vivo. This project will investigate the molecular mechanisms used by viral Tax to prevent the degradation of ICN1 and stimulate expression of its target genes. We will also examine the role of activated Notch in proliferation and inhibition of apoptosis in early phases of HTLV-I infection of T-cells.

Public Health Relevance

HTLV-I is associated with adult T-cell leukemia, an aggressive and fatal disease with very limited treatment options and no cure. This grant application aims to explore the mechanisms used by the human retrovirus HTLV-I Tax protein to stabilize Notch and induce constitutive Notch signaling through activation of the NF-kappaB pathway and IKK1. Since alterations in NF-kappaB signaling are frequently found in human cancers, our studies will help to better understand the regulatory pathways involved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI103851-02
Application #
8606171
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
2013-01-17
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$203,850
Indirect Cost
$68,850
Name
University of Kansas
Department
Pathology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160