Understanding DNA Damage Response and DNA Repair in Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma (MM), a malignant plasma cell disorder, is characterized by abnormal DNA damage response (DDR). MM cells adapt over time via gene mutations or chromosomal aberrations, including changes to DDR and DNA repair genes. Increased DNA repair and avoidance of DNA-damaged induced cellular death promote tumor formation, progression, and resistance to treatments. Because of the wide array of DDR and DNA repair mechanisms, DDR is an elusive target. Currently, treatments such as proteasome inhibitors and alkylating agents are commonly used in patients with MM. These treatments affect DDR and DNA repair pathways in different ways. As more studies are conducted, targeting DDR mechanisms might emerge as new treatments, as described in this review. ABSTRACT: Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated (ATM) loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.