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
Kiran K. Madugula,
Julie Joseph,
Catherine DeMarino,
Rashida Ginwala,
Vanessa Teixeira,
Zafar K. Khan,
Dominic Sales,
Sydney Wilson,
Fatah Kashanchi,
Amanda W. Rushing,
Isabelle Lemasson,
Edward W. Harhaj,
Murali Janakiram,
B. Hilda Ye,
Pooja Jain
Affiliations
Kiran K. Madugula
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
Julie Joseph
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
Catherine DeMarino
Laboratory of Molecular Virology, George Mason University, Manassas, VA, USA
Rashida Ginwala
Fox Chase Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
Vanessa Teixeira
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA; Instituto de Ciencias Biológicas, Universidad de Pernambuco, Recife, PE, Brazil
Zafar K. Khan
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
Dominic Sales
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
Sydney Wilson
Laboratory of Molecular Virology, George Mason University, Manassas, VA, USA
Fatah Kashanchi
Laboratory of Molecular Virology, George Mason University, Manassas, VA, USA
Amanda W. Rushing
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
Isabelle Lemasson
Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
Edward W. Harhaj
Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, USA
Murali Janakiram
Department of Oncology, Montefiore Medical Center
B. Hilda Ye
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
Pooja Jain
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
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.
