The Association of the DNA Repair Genes with Acute Myeloid Leukemia: The Susceptibility and the Outcome After Therapy

Abstract

Acute myeloid leukemia (AML), the most common acute leukemia in adults, is a clonal hemopoietic disorder that is frequently associated with genetic instability characterized by a diversity of chromosomal and molecular abnormalities. There are a lot of reports that show that human cancer can be initiated by DNA damage caused by ultraviolet (UV), ionizing radiation, and environmental chemical agents. Many genes encode proteins that function to protect cells against genetic instability through numerous mechanisms, including deoxyribonucleic acid (DNA) repair pathways and protection against oxidative stress. DNA repair pathways play an important role in maintaining the integrity of the genome, and it is obvious that defects in repair pathways are involved in many different types of diseases, including leukemia and cancer (Seedhouse, 2002). DNA damage repair and cell-cycle checkpoints are the most important defense mechanisms against mutagenic exposures. The most important DNA-repair pathways in human cells are: direct repair, base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), Double Strand Break Repair (DSB repair) and translesion DNA synthesis (TLS). Each pathway repairs a different type of lession (D'Andrea, 2010). The NER pathway mainly removes bulky distortions in the shape of the DNA double helix. The BER pathway is responsible for removal of oxidized DNA bases that may arise endogenously or from exogenous agents. The DSB pathway is responsible for repairing double-strand breaks caused by a variety of exposures, including ionizing radiation. There are two distinct and complementary pathways for DSB repair-namely, homologous recombination (HR) and nonhomologous end joining (NHEJ). Recent studies have suggested that DNA damage was related to the pathogenesis of some diseases such as AML. Therefore, some DNA repair genes may be involved in AML susceptibility (Allan, 2004; Kuptsova, 2007; Seedhouse, 2002, 2004; Voso, 2007). Exposure to carcinogenic and genotoxic compounds causes DNA damage, and the cells have developed multiple DNA repair pathways to protect themselves from different types of DNA damage.