Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by expansion of myeloid blasts that fail to differentiate normally. This leads to hematopoietic failure resulting in granulocytopenia, thrombocytopenia, or anemia. (Leuk Res 2021 Lancet 2006 NEJM 1999). Chromosomal abnormalities and genetic mutations in AML cells are associated with aberrant proliferation and/or blockade of normal differentiation of hematopoietic cells. (J Mol Med (Berl). 2020) DNA damage repair mechanisms are essential for maintaining genomic integrity, and abnormalities in DNA repair genes may increase the risk of developing cancer. Recently, we reported the association between 8-oxoG glycosylase1 (OGG1), a key player in the base excision repair (BER) pathway, and the prognosis of AML. In this paper, we further investigate the relationship between BER pathway-related genes and the pathogenesis of AML.
Genomic DNA is constantly damaged by endogenous reactive oxygen species and metabolites, as well as by various environmental agents such as ionizing radiation, ultraviolet light, and chemical compounds. The BER pathway is responsible for repairing most endogenous small DNA damage, including deamination, depurination, alkylation, and oxidative damage, which occurs approximately 30,000 times per cell per day. (Nature1993. Cancer Lett 2012.) Four proteins are involved in BER pathway: DNA glycosylases, AP endonuclease or AP DNA lyase, DNA polymerase, and DNA ligase. In this study, we focused on four BER genes: APEX1, MUTYH, OGG1, and XRCC1. APEX1 has multiple functions and acts as an AP endonuclease in BER; MUTYH and OGG1 are DNA glycosylases; XRCC1 is a scaffold protein that binds DNA polymerase and DNA ligase (Cell. Mol. Life Sci. 66 (2009). Numerous studies have reported the association between functional BER gene polymorphisms and the risk of various tumors, including lung, digestive system, bladder, and breast cancers. (Med Oncol. 2015, Mol Biol Rep 2014, PLoS One 2013, Diagn Pathol 2012). Previous studies have also reported associations between XRCC1 polymorphisms and AML risk. However, few studies have comprehensively investigated the impact of BER polymorphisms on the pathogenesis of AML. (Mol Carcinog. 2017, Blood 2007, Int J Cancer 2011). In this study, we focused on six BER polymorphisms and their impact on the development and clinical features of AML: APEX1 -656T>G (rs1760944), APEX1 D148E (rs1130409), MUTYH Q324H (rs3219489), OGG1 S326C (rs1052133), XRCC1 R194W (rs1799782), and XRCC1 R399Q (rs25487).
In the present study, we found an association between the risk of developing AML and APEX1 polymorphisms. Therefore, we further investigated the association between APEX1 and AML pathogenesis, considering that APEX1 has a positive influence on AML. APEX1, also known as redox factor-1 (Ref-1), is a multifunctional protein with both DNA repair and transcriptional regulatory activities (Antioxid Redox Signal. 2009, Antioxid Redox Signal. 2014). APEX1 is frequently upregulated in various tumors and its expression is associated with clinical stage and poor prognosis in several tumors, including lung cancer, breast cancer, hepatocellular carcinoma, bladder cancer and multiple myeloma (Lung Cancer 2009, Biochem Biophys Res Commun 2012, Clin Cancer Res 2005, Mol Med 2007, Clin Lymphoma Myeloma Leuk 2010). In AML, Vascotto et al. and López et al. reported the interaction of APEX1 and NPM1, which are frequently mutated in AML cells. However, little is known about the role of APEX1 in the pathogenesis of AML. However, little is known about the role of APEX1 in the overall pathogenesis of AML.
In the present study, we found an association between the risk of developing AML and APEX1 polymorphisms. Therefore, we further investigated the association between APEX1 and AML pathogenesis, considering that APEX1 has a positive influence on AML. APEX1, also known as redox factor-1 (Ref-1), is a multifunctional protein with both DNA repair and transcriptional regulatory activities (Antioxid Redox Signal. 2009, Antioxid Redox Signal. 2014). APEX1 is frequently upregulated in various tumors and its expression is associated with clinical stage and poor prognosis in various tumors, including lung, breast, hepatocellular, bladder and multiple myeloma (Lung Cancer 2009, Biochem Biophys Res Commun 2012, Clin Cancer Res 2005, Mol Med 2007, Clin Lymphoma Myeloma Leuk 2010). In AML, Vascotto et al. and López et al. reported the interaction of APEX1 and NPM1, which are frequently mutated in AML cells. However, little is known about the role of APEX1 in the pathogenesis of AML. However, little is known about the role of APEX1 in the overall pathogenesis of AML.
The aim of this study was to investigate the impact of BER polymorphisms on susceptibility, prognosis, and clinical features in AML patients. In addition to the analysis of these polymorphisms, the impact of APEX1, a multifunctional protein, on the pathogenesis of AML was also investigated. Our study was divided into two main parts: the analysis of BER polymorphisms and the investigation of APEX1 expression and its impact on knockdown.