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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood
200 umbilical cord blood (UCB) probands were screened for the presence of the most common pre-leukemic fusion genes (PFG) associated with childhood B-cell ALL using the real-time quantitative polymerase chain reaction (RT-qPCR) method with a sensitivity of approximately 1–3 copies per 100,000 cells [14]
From the total number of 500 UCB probands, 133 probands were tested positive, i.e. PFG was found at least in one of triplicate samples by the primary RTqPCR. 92 probands were positive for BCR-ABL1, 45 for ETV6-RUNX1, and 16 for MLL-AF4 (Figure 1A)
Summary
Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. ALL arises from clonal proliferation of hematopoietic stem cell/ progenitor cell (HSPC), replacing normal hematopoietic cells in the bone marrow (BM) [1, 2]. The resultant fusion gene product with a novel activity, different from the activities of individual partner genes, produces a persistent, but covert pre-leukemic clone [10,11,12] In their pioneer study, the Greaves’ group reported ~1.06% incidence of TEL-AML1/ETV6RUNX1, the most common ALL-associated PFG, in umbilical cord blood (UCB) samples from England and Italy [10]. The Greaves’ group reported ~1.06% incidence of TEL-AML1/ETV6RUNX1, the most common ALL-associated PFG, in umbilical cord blood (UCB) samples from England and Italy [10] These data were further confirmed by other groups by screening UCB of newborns from Czech Republic, Japan, USA, and Slovakia [10, 13, 14] but challenged by the Danish group reporting that the incidence of ETV6-RUNX1 is the same as the incidence of ETV6-RUNX1 related ALL [15]. Validation of the PFG incidence in UCB become of critical importance for leukemia risk estimation and diagnostics
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