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

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-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 knock-down 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 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.

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