The Oncoprotein Fra-2 Drives the Activation of Human Endogenous Retrovirus Env Expression in Adult T-Cell Leukemia/Lymphoma (ATLL) Patients

TL;DR

A cancer-related protein called Fra-2 activates ancient viral genes in a rare and aggressive leukemia, which may explain its resistance to treatment and offer new treatment ideas.

Contribution

The study identifies Fra-2 as a driver of HERV activation in ATLL, linking it to disease progression and chemoresistance.

Findings

HERV genes are highly upregulated in acute ATLL compared to asymptomatic HTLV-1 carriers.

Fra-2 binds to the LTR region of HERV families like HERV-H and HERV-K, activating their transcription.

Aberrant HERV expression may contribute to ATLL development and chemoresistance.

Abstract

Human endogenous retroviruses (HERVs) are retroviral sequences integrated into 8% of the human genome resulting from ancient exogenous retroviral infections. Unlike endogenous retroviruses of other mammalian species, HERVs are mostly replication and retro-transposition defective, and their transcription is strictly regulated by epigenetic mechanisms in normal cells. A significant addition to the growing body of research reveals that HERVs’ aberrant activation is often associated with offsetting diseases like autoimmunity, neurodegenerative diseases, cancers, and chemoresistance. Adult T-cell leukemia/lymphoma (ATLL) is a very aggressive and chemoresistant leukemia caused by the human T-cell leukemia virus type 1 (HTLV-1). The prognosis of ATLL remains poor despite several new agents being approved in the last few years. In the present study, we compare the expression of HERV genes in CD8+-depleted PBMCs from HTLV-1 asymptomatic carriers and patients with acute ATLL. Herein, we show that HERVs are highly upregulated in acute ATLL. Our results further demonstrate that the oncoprotein Fra-2 binds the LTR region and activates the transcription of several HERV families, including HERV-H and HERV-K families. This raises the exciting possibility that upregulated HERV expression could be a key factor in ATLL development and the observed chemoresistance, potentially leading to new therapeutic strategies and significantly impacting the field of oncology and virology.

Figures