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.

Retroviral b‐Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation

“…Although it remains unclear which cell types are predominantly responsible for the release of each analyte, due to the scarce nature of readily available HAM/TSP patient samples, further studies on sera from patients that interrogate each immune cell‐type are limited. However, alternative research routes via HTLV‐1 infected cell systems previously described (Madugula et al., 2022 ) and using a unique HAM/TSP like cell system, OSP2 cells, have been crucial to establish our basic understanding of the ICP molecules in HTLV‐1 infection and disease. OSP2 cells demonstrated the presence of analytes with similar expression patterns as HAM/TSP patients.…”

“…HTLV‐1 negative Jurkat cells, and HTLV‐1 transformed leukaemia like cells ATL‐ED (often referred as ED‐405(‐)) and MT‐4 cultures were maintained as described previously (Madugula et al., 2022 ). The OSP2 (HAM/TSP‐derived) cell cultures were acquired through the NIH AIDS Reagent Program (Cat.…”

“…All study participants gave written informed consent to participate in UCSF-HOST and approval was obtained from the University's human program studies to conduct analyses on banked specimens. HTLV-1 negative Jurkat cells, and HTLV-1 transformed leukaemia like cells ATL-ED (often referred as ED-405(-)) and MT-4 cultures were maintained as described previously (Madugula et al, 2022). The OSP2 (HAM/TSP-derived) cell cultures were acquired through the NIH AIDS Reagent Program (Cat.…”

Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2

“…Additional insight on the regulation of HTLV-1 antisense promoter comes from recent studies from authors' laboratories on a unique transcription factor called Myocyte Enhancer Factor (MEF)-2 that was previously established to have a role in HTLV-1 pathogenesis (Jain et al, 2015). More recent studies investigated all four MEF-2 isoforms (A-D, reviewed in (Madugula et al, 2022)), of which two (MEF-2A and -2C) were highly overexpressed in a wide array of HTLV-1 infected and ATLL cell lines as well as in acute ATLL patients (Madugula et al, 2022). Knockdown of these isoforms led to decreased cell proliferation and regulated cell cycle progression.…”

The Pleiotropic Effects of YBX1 on HTLV-1 Transcription

“…Despite the frequent loss of 5 LTR transcriptional activity, the 3 LTR (which encodes for HBZ) remains transcriptionally active in cell lines, patients infected with HTLV-1, and ATL disease patients [13]. Transcription from the 3 LTR antisense promoter is regulated by factor SP1 (specificity protein 1), JunD, and MEF-2C (myocyte enhancer factor 2C) binding sites located in the promoter region [13,[23][24][25][26][27]. Recent reports have suggested the 3 region of the provirus remains transcriptionally active in part due to a viral CTCF (CCCTC-binding factor) binding site [28] and an internal enhancer element [29,30].…”