Adult T cell leukemia-lymphoma (ATLL) is an aggressive and generally fatal tumor associated with Human T cell Leukemia Virus Type 1 (HTLV-1). ATLL, a CD4 helper T cell malignancy, presents clinically as either a chronic disease that may progress, as an acute leukemia or high grade lymphoma. ATLL pafients fare very pooriy with conventional chemotherapeutic regimens, however therapy with azidothymidine (AZT) and interferon alpha (IFN-a) has produced long-term clinical remissions in a subset of patients. Little is known of the molecular pathogenesis of ATLL. Suitable animal models for the disease have been lacking and HTLV-1 transformed lines differ substanfially from the primary tumors. Most research has centered on the role of the viral oncoprotein tax although it is not expressed in primary tumors. Research on HTLV-1 and oncogenesis is further complicated by the prolonged latency between the time of infection and the development of overt disease. In order to study this tumor and identify subgroups of ATLL that may be amenable to AZT/IFNo (or other) therapies one must have access to a large number of primary isolates. HTLV-1 related diseases are a significant health care problem in certain US communities, in afro-Caribbean and afro-Latin communities. Miami is an endemic area for the HTLV-1 virus as is Salvador, the capital of the northeastern Brazilian state, Bahia. Through a collaboration between the University of Miami and the Federal University of Bahia we have identified several important molecular features related to the pathogenesis, therapy and prognosis of ATLL. We have defined two forms of the disease, one that is responsive to AZT/IFNa and another that is resistant. Response or lack thereof correlates with nuclear NF-kB subunit composifion and IFN signaling properties. We have also found that patients in remission while on long-term antiviral therapy have persistent T cell clones detectable in peripheral blood mononuclear cells (PBMC's). We propose to study primary ATLL in pafients at our institution and at our collaborators site. We will follow patients enrolled on an anfiviral clinical trial to determine the molecular characteristics of sensitive and resistant disease. This translational study which is thematically linked to this overall proposal (IFN and innate immune signaling) has great potential to begin to elucidate the molecular processes of ATLL progression as well as define the subset of pafients most likely to benefit from therapy.

Public Health Relevance

HTLV-1 related ATLL is a deadly disease that predominanfiy affects Afro-Caribbean and African Americans in our community (South Florida). The disease is also quite common in Afro-Lafin populafions. The study of ATLL presents some technical difficulties and investigation of the actual tumor requires access to primary pafient material. We present in our proposal a translafional study of the biology of AZT/IFNa sensifive and resistant ATLL coupled with a clinical trial. We have substanfial experience with this disease and our project is closely integrated with the two other proposals in this application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA128115-03
Application #
8322079
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$245,058
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Zhou, Qinjie; Lavorgna, Alfonso; Bowman, Melissa et al. (2015) Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon. J Biol Chem 290:14729-39
Betancourt, Dillon; Ramos, Juan Carlos; Barber, Glen N (2015) Retargeting Oncolytic Vesicular Stomatitis Virus to Human T-Cell Lymphotropic Virus Type 1-Associated Adult T-Cell Leukemia. J Virol 89:11786-800
Bayraktar, Ulas Darda; Diaz, Luis A; Ashlock, Brittany et al. (2014) Zidovudine-based lytic-inducing chemotherapy for Epstein-Barr virus-related lymphomas. Leuk Lymphoma 55:786-94
Gao, Linlin; Harhaj, Edward William (2013) HSP90 protects the human T-cell leukemia virus type 1 (HTLV-1) tax oncoprotein from proteasomal degradation to support NF-?B activation and HTLV-1 replication. J Virol 87:13640-54
Charoenthongtrakul, Soratree; Gao, Linlin; Parvatiyar, Kislay et al. (2013) RING finger protein 11 targets TBK1/IKKi kinases to inhibit antiviral signaling. PLoS One 8:e53717
Bhatt, Shruti; Ashlock, Brittany M; Toomey, Ngoc L et al. (2013) Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest 123:2616-28
Lavorgna, Alfonso; Harhaj, Edward W (2013) Is there a role for ubiquitin or SUMO in human T-cell leukemia virus type 2 Tax-induced NF-*B activation? Future Virol 8:223-227
Shembade, Noula; Harhaj, Edward W (2012) Regulation of NF-?B signaling by the A20 deubiquitinase. Cell Mol Immunol 9:123-30
Lavorgna, Alfonso; Harhaj, Edward W (2012) EBV LMP1: New and shared pathways to NF-ýýB activation. Proc Natl Acad Sci U S A 109:2188-9
Harhaj, Edward W; Dixit, Vishva M (2012) Regulation of NF-?B by deubiquitinases. Immunol Rev 246:107-24

Showing the most recent 10 out of 21 publications