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Role of retroelements in haematopoiesis during haematopoietic stem cell ageing and in leukaemia: friend or foe? Volume 29, issue 1, Janvier-Février 2023

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Authors
Inserm U1287, Institut Gustave Roussy, 94805 Villejuif
* Tirés à part : F. Porteu
Liens d’intérêt : Les auteurs déclarent n’avoir aucun lien d’intérêt en rapport avec cet article.

Retrotransposable elements (REs), comprising endogenous retroviruses (ERV), and long or short interspersed elements (LINE-1; SINE), account for nearly half of human genomes. REs are regulated by heterochromatin, a condensed state of DNA characterized by DNA methylation and repressive histone marks such as H3K9me2, H3K9me3 and H3K27me3. Described for a long-time as junk DNA, they are gaining more and more interest, especially in aging and cancer where the chromatin is disorganized. REs can spread in the genome through a copy/paste mechanism, constituting a great source of genomic instability. They are also major contributors of gene regulatory networks, providing alternative promoters, splicing or polyadenylation signals, and also by serving as cis-regulatory elements in a cell- and tissue-specific manner. It is related to the progressive loss of heterochromatin. Defects in RE repression are also observed in cancer. Cancer cells become dependent on REs because of their ability to induce genomic instability and deregulate the transcriptome. Epigenetic reactivation of cryptic regulatory sequences within existing REs leads to widespread expression of oncogenes. However, REs are double-edged swords for cancer. Indeed, through their ability to mimic a viral state, leading to type I interferon (IFN-I) activation, REs can trigger apoptotic and antiproliferative signaling. Cancer therapies such as chemotherapy, radiation therapy, immunotherapy and DNA hypomethylating agents (HMAs) use this vulnerability to kill cancer cells. Because RE expression can be their Achilles heel, tumor cells develop mechanisms to prevent RE release from epigenetic repression. AML leukemic stem cells have low RE expression and inactivate immune pathways, which may be involved in their immune evasion. Epigenetic players such as MPP8 and SETDB1 have been identified as playing a major role in RE repression and their dysfunction is associated with leukemogenesis. The failure of HMA treatments to eliminate mutated clones observed in myelodysplastic syndromes could be due to the lack of RE induction. Here we discuss the different mechanisms that could prevent RE expression in leukemic stem cells, the importance of these elements in cell function, oncogenesis and immunity, highlighting the influence of epigenetic mechanisms in the regulation of ER expression and how they can be exploited in a therapeutic context.