A study of meiomitosis and novel pathways of genomic instability in cutaneous T-cell lymphomas (CTCL)
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Matthew Tsang1,*, Jennifer Gantchev2,*, Elena Netchiporouk2, Linda Moreau2, Feras M. Ghazawi1, Steven Glassman1, Denis Sasseville2 and Ivan V. Litvinov1,2
1Division of Dermatology, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada
2Division of Dermatology, McGill University, Montréal, Québec H4A 3J1, Canada
*These authors have contributed equally to this work
Ivan V. Litvinov, email: [email protected]
Denis Sasseville, email: [email protected]
Keywords: genomic instability; meiomitosis; cutaneous T-cell lymphomas; LINE-1; DNA double strand breaks
Received: August 20, 2018 Accepted: December 04, 2018 Published: December 28, 2018
Genomic instability is a hallmark of cancer and an enabling factor for genetic alterations that drive cancer development and progression. The clashing of mitosis and aberrantly expressed meiosis machineries, which may contribute to genomic instability, has been coined cancer “meiomitosis”. LINE-1 retrotransposition, a process active in germ cells, acts outside of the meiotic machinery to create DNA double strand breaks (DNA DSBs) and has played an important role in the evolution of the human genome. We have previously demonstrated that in CTCL several cancer testis/meiotic genes are expressed. Furthermore, this cancer exhibits extensive and ongoing chromosomal/microsatellite instability. In this study we analyzed immortalized patient-derived cells and primary CTCL patient samples using RT-PCR, western blotting and confocal microscopy and found that proteins critically involved in meiosis and LINE-1 retrotransposition are expressed and are associated with chromosomal instability and DNA DSB formation. Using cell cycle synchronization, we show G1/S phase-transition-specific expression of meiosis proteins. Using the Alu retrotransposition assay, we demonstrate the functional activity of LINE-1 retrotransposon in CTCL. Histone acetyltransferase inhibition results in downregulation of the ectopic germ cell programs and concomitant decrease in DNA DSBs foci formation. Notably, LINE-1 and meiosis genes were expressed across a panel of other solid tumor cell lines. Taken together, our results indicate that malignant cells in culture undergo “cancer meiomitosis” rather than the classic mitosis division. The ectopic expression of meiosis genes and reactivation of LINE-1 may be contributing to genomic instability and represent novel targets for immunotherapy in this and other cancers.
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