Demonstration of the non-random integration of HTLV-1/BLV proviruses in leukemia

HTLV-1 and BLV are world-wide distributed retroviruses that cause leukemia of 5% of infected individuals after a prolonged incubation period.  It was assumed that viral-encoded proteins initiate tumorigenesis (independently of the proviral integration site which was thought to be random), which is then exacerbated/complemented by the subsequent accumulation of somatic mutations in cancer driver genes. Using NGS-based methods allowing us to identify tens to hundreds of thousands of proviral integration sites, we show that these are not randomly distributed but rather concentrated in hotspots located in the vicinity of cancer drivers that are perturbed in part by the formation of virus-host chimeric transcripts.  These hotspots are thought to reflect clonal selection resulting from an advantage conferred as a result of cancer driver perturbation.  Proviral integration patterns are characterized by marked polarity that is uncovering the regulation of protein coding genes either directly or by adjacent non-coding transcripts.

We have developed a new method exploiting CRISPR/Cas9 and long read NGS (f.i. Oxford Nanopore technology) for more effective massive parallel sequencing of proviruses with cognate integration sites that opens up a wealth of new opportunities.

Key publications

Pooled CRISPR Inverse PCR sequencing (PCIP-seq): simultaneous sequencing of retroviral insertion points and the associated provirus in thousands of cells with long reads. Artesi M$, Hahaut V$, Ashrafi F, Marçais A, Hermine O, Griebel P,  Arsic N, van der Meer F, Burny A, Bron D, Charlier C, Georges M, Van den Broeke A#, Durkin K#bioRxiv 558130; doi: (2019)

Monitoring Molecular Response in Adult T-cell Leukemia/Lymphoma by High-Throughput Sequencing Analysis of HTLV-1 Clonality. Artesi M, Marçais A, Durkin K, Rosewick N, Hahaut V, Suarez P, Trinquand A, Lhermitte L, Avettand Fenoel V, Georges M, Hermine O & Van den Broeke ALeukemia 31: 2532-2535 (2017)

Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis. Rosewick N, Durkin K, Marçais A, Artesi M, Hahaut V, Griebel P, Arsic N, Avettan-Fenoel V, Burny A, Charlier C, Hermine O, Georges M, Van den Broeke ANat Commun 8: 15264 (2017)

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