Journal article
Regulation of human T-cell leukemia virus type 1 antisense promoter by myocyte enhancer factor-2C in the context of adult T-cell leukemia and lymphoma
Haematologica (Roma), v 107(12), pp 2928-2943
01 Dec 2022
PMID: 35615924
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Adult T-cell leukemia and lymphoma (ATLL) is an intractable T-cell neoplasia caused by a retrovirus, namely human T-cell leukemia virus type 1 (HTLV-1). Patients suffering from ATLL present a poor prognosis and have a dearth of treatment options. In contrast to the sporadic expression of viral transactivator protein Tax present at the 5' promoter region long terminal repeats (LTR), HTLV-1 bZIP gene (HBZ) is encoded by 3'LTR (the antisense promoter) and maintains its constant expression in ATLL cells and patients. The antisense promoter is associated with selective retroviral gene expression and has been an understudied phenomenon. Herein, we delineate the activity of transcription factor MEF (myocyte enhancer factor)-2 family members, which were found to be enriched at the 3'LTR and play an important role in the pathogenesis of ATLL. Of the four MEF isoforms (A to D), MEF-2A and 2C were highly overexpressed in a wide array of ATLL cell lines and in acute ATLL patients. The activity of MEF-2 isoforms were determined by knockdown experiments that led to decreased cell proliferation and regulated cell cycle progression. High enrichment of MEF-2C was observed at the 3'LTR along with cofactors Menin and JunD resulting in binding of MEF-2C to HBZ at this region. Chemical inhibition of MEF-2 proteins resulted in the cytotoxicity of ATLL cells in vitro and reduction of proviral load in a humanized mouse model. Taken together, this study provides a novel mechanism of 3'LTR regulation and establishes MEF-2 signaling a potential target for therapeutic intervention for ATLL.
Metrics
Details
- Title
- Regulation of human T-cell leukemia virus type 1 antisense promoter by myocyte enhancer factor-2C in the context of adult T-cell leukemia and lymphoma
- Creators
- Kiran K. Madugula - Drexel UniversityJulie Joseph - Drexel UniversityCatherine DeMarino - George Mason UniversityRashida Ginwala - Thomas Jefferson UniversityVanessa Teixeira - Drexel UniversityZafar K. Khan - Drexel UniversityDominic Sales - Drexel UniversitySydney Wilson - George Mason UniversityFatah Kashanchi - George Mason UniversityAmanda W. Rushing - East Carolina UniversityIsabelle Lemasson - East Carolina UniversityEdward W. Harhaj - Penn State Milton S. Hershey Medical CenterMurali Janakiram - Montefiore Medical CenterHilda Ye - Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY USAPooja Jain - Drexel University
- Publication Details
- Haematologica (Roma), v 107(12), pp 2928-2943
- Publisher
- Ferrata Storti Foundation
- Number of pages
- 16
- Grant note
- NIH AIDS reagents program; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine
- Web of Science ID
- WOS:000917249000019
- Scopus ID
- 2-s2.0-85143180078
- Other Identifier
- 991020545125004721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Hematology