Oncotarget

Research Papers:

Low numbers of pre-leukemic fusion genes are frequently present in umbilical cord blood without affecting DNA damage response

Pavol Kosik, Milan Skorvaga, Matus Durdik, Lukas Jakl, Ekaterina Nikitina, Eva Markova, Katarina Kozics, Eva Horvathova and Igor Belyaev _

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Oncotarget. 2017; 8:35824-35834. https://doi.org/10.18632/oncotarget.16211

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Abstract

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

Correspondence to:

Igor Belyaev, email: Igor.Beliaev@savba.sk

Keywords: pre-leukemic fusion genes, stem cells, DNA damage response, apoptosis

Received: November 18, 2016     Accepted: March 08, 2017     Published: March 15, 2017

ABSTRACT

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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