DNA damage signalling from the placenta to foetal blood as a potential mechanism for childhood leukaemia initiation

Els Mansell; Nahid Zareian; Camille Malouf; Chrysa Kapeni; Natalie Brown; Christopher Badie; Duncan Baird; Jon D Lane; Katrin Ottersbach; Allison Blair; C Patrick Case

doi:10.1038/s41598-019-39552-0

DNA damage signalling from the placenta to foetal blood as a potential mechanism for childhood leukaemia initiation

Els Mansell, Nahid Zareian, Camille Malouf, Chrysa Kapeni, Natalie Brown, Christopher Badie, Duncan Baird, Jon D Lane, Katrin Ottersbach, Allison Blair, C Patrick Case

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Abstract

For many diseases with a foetal origin, the cause for the disease initiation remains unknown. Common childhood acute leukaemia is thought to be caused by two hits, the first in utero and the second in childhood in response to infection. The mechanism for the initial DNA damaging event are unknown. Here we have used in vitro, ex vivo and in vivo models to show that a placental barrier will respond to agents that are suspected of initiating childhood leukaemia by releasing factors that cause DNA damage in cord blood and bone marrow cells,
including stem cells. We show that DNA damage caused by in utero exposure can reappear postnatally after an immune challenge. Furthermore, both foetal and postnatal DNA damage are prevented by prenatal exposure of the placenta to a mitochondrially-targeted antioxidant.
We conclude that the placenta might contribute to the first hit towards leukaemia initiation by bystander-like signalling to foetal haematopoietic cells.

Original language	English
Article number	4370
Number of pages	17
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-39552-0
Publication status	Published - 13 Mar 2019

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abstract = "For many diseases with a foetal origin, the cause for the disease initiation remains unknown. Common childhood acute leukaemia is thought to be caused by two hits, the first in utero and the second in childhood in response to infection. The mechanism for the initial DNA damaging event are unknown. Here we have used in vitro, ex vivo and in vivo models to show that a placental barrier will respond to agents that are suspected of initiating childhood leukaemia by releasing factors that cause DNA damage in cord blood and bone marrow cells,including stem cells. We show that DNA damage caused by in utero exposure can reappear postnatally after an immune challenge. Furthermore, both foetal and postnatal DNA damage are prevented by prenatal exposure of the placenta to a mitochondrially-targeted antioxidant.We conclude that the placenta might contribute to the first hit towards leukaemia initiation by bystander-like signalling to foetal haematopoietic cells.",

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AU - Zareian, Nahid

AU - Malouf, Camille

AU - Kapeni, Chrysa

AU - Brown, Natalie

AU - Badie, Christopher

AU - Baird, Duncan

AU - Lane, Jon D

AU - Ottersbach, Katrin

AU - Blair, Allison

AU - Case, C Patrick

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AB - For many diseases with a foetal origin, the cause for the disease initiation remains unknown. Common childhood acute leukaemia is thought to be caused by two hits, the first in utero and the second in childhood in response to infection. The mechanism for the initial DNA damaging event are unknown. Here we have used in vitro, ex vivo and in vivo models to show that a placental barrier will respond to agents that are suspected of initiating childhood leukaemia by releasing factors that cause DNA damage in cord blood and bone marrow cells,including stem cells. We show that DNA damage caused by in utero exposure can reappear postnatally after an immune challenge. Furthermore, both foetal and postnatal DNA damage are prevented by prenatal exposure of the placenta to a mitochondrially-targeted antioxidant.We conclude that the placenta might contribute to the first hit towards leukaemia initiation by bystander-like signalling to foetal haematopoietic cells.

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DNA damage signalling from the placenta to foetal blood as a potential mechanism for childhood leukaemia initiation

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