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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

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 trans...

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Published in:Haematologica (Roma) 2022-12, Vol.107 (12), p.2928-2943
Main Authors: Madugula, Kiran K, Joseph, Julie, DeMarino, Catherine, Ginwala, Rashida, Teixeira, Vanessa, Khan, Zafar K, Sales, Dominic, Wilson, Sydney, Kashanchi, Fatah, Rushing, Amanda W, Lemasson, Isabelle, Harhaj, Edward W, Janakiram, Murali, Ye, B Hilda, Jain, Pooja
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cited_by cdi_FETCH-LOGICAL-c474t-18d148ed3638cfcda74894d68dc1e07388bdf3fca05b86b1e09d580c03961f003
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container_issue 12
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container_title Haematologica (Roma)
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creator Madugula, Kiran K
Joseph, Julie
DeMarino, Catherine
Ginwala, Rashida
Teixeira, Vanessa
Khan, Zafar K
Sales, Dominic
Wilson, Sydney
Kashanchi, Fatah
Rushing, Amanda W
Lemasson, Isabelle
Harhaj, Edward W
Janakiram, Murali
Ye, B Hilda
Jain, Pooja
description 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.
doi_str_mv 10.3324/haematol.2021.279542
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subjects Animals
Human T-lymphotropic virus 1 - genetics
Human T-lymphotropic virus 1 - metabolism
Humans
Leukemia-Lymphoma, Adult T-Cell - pathology
Lymphoma - genetics
MEF2 Transcription Factors - genetics
MEF2 Transcription Factors - metabolism
Mice
Promoter Regions, Genetic
T-cell Leukemia/lymphoma
Viral Proteins - genetics
Viral Proteins - metabolism
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
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