Low numbers of pre-leukemic fusion genes are frequently present in umbilical cord blood without affecting DNA damage response
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Pavol Kosik1,*, Milan Skorvaga1,*, Matus Durdik1, Lukas Jakl1, Ekaterina Nikitina1,2, Eva Markova1, Katarina Kozics1, Eva Horvathova1, Igor Belyaev1
1Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
2Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences, Tomsk, Russia
*These authors contributed equally to this work
Igor Belyaev, email: [email protected]
Keywords: pre-leukemic fusion genes, stem cells, DNA damage response, apoptosis
Received: November 18, 2016 Accepted: March 08, 2017 Published: March 15, 2017
Despite widely accepted notion that many childhood leukemias are likely developed from hematopoietic stem/progenitor cells (HSPC) with pre-leukemic fusion genes (PFG) formed in embryonic/fetal development, the data on PFG incidence in newborns are contradictive. To provide a better understanding of a prenatal origin of leukemia, umbilical cord blood from 500 newborns was screened for the presence of the most frequent PFG associated with pediatric B-cell acute lymphoblastic leukemia. This screening revealed relatively high incidence of ETV6-RUNX1, BCR-ABL1 (p190) and MLL-AF4 at very low frequencies, averaging ~14 copies per 100,000 cells. We assume that most of these PFG might originate relatively late in embryonic/fetal development and will be eliminated later during postnatal development. The obtained results suggested that higher PFG copy numbers originating in specific time windows of the hematopoietic stem cell hierarchy may define a better prognostic tool for the assessment of leukemogenic potential. We have observed no significant effect of low-copy PFG on radiation-induced DNA damage response, accumulation of endogenous DNA double-stranded breaks, and apoptosis in either lymphocytes or HSPC. Imaging flow cytometry showed lower level of γH2AX foci in HSPC in comparison to lymphocytes suggesting better protection of HSPC from DNA damage.
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