XRCC4 rs28360071 intronic variant is associated with increased risk for infant acute lymphoblastic leukemia with KMT2A rearrangements

Abstract

Early age acute leukemia (EAL) shows a high frequency of KMT2A-rearrangements (KMT2A-r). Previous investigations highlighted double-strand breaks arising from maternal exposure to xenobiotics during pregnancy as a risk factor for EAL and KMT2A-r. In this case-control study, we investigated the relationship between EAL and genetic variants of the nonhomologous end-joining (XRCC6 rs5751129, XRCC4 rs6869366 and rs28360071), since they might affect DNA repair capacity, leading to KMT2A-r and leukemogenesis. Samples from 577 individuals (acute lymphoblastic leukemia-ALL, n=164; acute myeloid leukemia-AML, n=113; controls, n=300) were genotyped. No significant association was found for rs5751129 and rs6869366, whereas rs28360071 was associated with an increased risk for ALL with KMT2A-r (IIxID: OR-Odds ratio 2.23, CI 1.17-4.25, p=0.014). Bone marrow samples from ALL patients showed a higher expression of XRCC4 compared to AML patients (p=0.025). Human Splicing Finder 3.1 predicted that the deleted allele of rs28360071 is potentially associated with the activation of a 5' cryptic splice site in intron 3 of XRCC4. The sequencing of cDNA did not show any differences on the splicing process for the rs28360071 genotypes. Our results suggest that the deleted allele for rs28360071 increases the risk for ALL with KMT2A-r, but not by modifying the XRCC4 expression levels or its structure.

Non-homologous End-joining Genotype, mRNA Expression, and DNA Repair Capacity in Childhood Acute Lymphocytic Leukemia

“…In accordance with the existing literature, XRCC4 rs3734091 and rs28360071 are located within amino acidcoding and intronic regions, respectively (43,44). XRCC5 rs828907 and XRCC6 rs5751129 are located within the promoter region of their respective genes (45,46). Our investigation into mRNA expression of these ALLsusceptibility genes revealed that only the C allele of XRCC6 rs5751129 was significantly associated with a decrease in its mRNA transcripts (Figure 2).…”

Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia

“…The importance of AML cell CK2 levels for various hallmarks of cancer is reviewed and discussed in this section. The effects of CK2 inhibition in human AML cells are summarized in Table 2 [55][56][57][58][59][60][61][62][63][64][65][66][67][68], and they are discussed in more detail in the following subsections. Table 2.…”

“…Table 2. A summary of the important molecular and functional effects of CK2 inhibition in AML cells; an overview of the molecular effects and modulation of organellar functions [55][56][57][58][59][60][61][62][63][64][65][66][67][68]. The effects are discussed in more detail in Sections 6.1-6.5.…”

“…Furthermore, Wnt signaling is also important for leukemogenesis/chemosensitivity in human AML [29,30]. Finally, the DNA damage response proteins Xrcc1, Xrcc4, and Mdc1 are also important for leukemogenesis/chemosensitivity in human AML [57][58][59][60], and their phosphorylation is regulated by CK2 [3,55]. Thus, PI3K-Akt, Jak-Stat, NFκB, and Wnt signaling, as well as DNA damage responses, seem to be important substrates for CK2 in human AML cells.…”