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DNA Damage Response in Multiple Myeloma: the Role of the Tumor Microenvironment

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DNA Damage Response in Multiple Myeloma: the Role of the Tumor Microenvironment cancers Review DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment Takayuki Saitoh 1,* and Tsukasa Oda 2 1 Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan 2 Laboratory of Molecular Genetics, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan; [email protected] * Correspondence: [email protected] Simple Summary: Multiple myeloma (MM) is a plasma cell malignancy. Novel therapies have improved outcomes in MM patients; however, MM still remains incurable. MM cells present genomic instability, whose molecular basis is not fully understood. Recently, it has been reported that the DNA damage response (DDR) may influence genomic changes and drug resistance in MM. An abnormal DNA repair function may provide an alternative explanation for genomic instability. In this review, we show an overview of the DNA repair pathways and discuss the role of the tumor microenvironment in governing the DNA repair mechanisms. The tumor microenvironment factors, such as hypoxia and inflammation, and chemotherapeutic agents profoundly influence the DNA repair pathways in MM. Abstract: Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this Citation: Saitoh, T.; Oda, T. DNA disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, Damage Response in Multiple influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, Myeloma: The Role of the Tumor and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate Microenvironment. Cancers 2021, 13, genomic instability and aberrant features that enable MM progression and drug resistance. This 504. https://doi.org/10.3390/ review provides an overview of the DNA repair pathways, with a special focus on their function in cancers13030504 MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms. Academic Editor: Aline Bozec Keywords: multiple myeloma; DNA repair; genomic instability; DNA damage response; base Received: 14 December 2020 excision repair; homologous recombination Accepted: 26 January 2021 Published: 28 January 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- Multiple myeloma (MM), which accounts for 1% of all cancers and approximately iations. 10% of all hematologic malignancies, is characterized by the clonal proliferation of plasma cells [1,2]. The development and introduction of therapeutics, such as the immunomodula- tory drugs thalidomide and lenalidomide and the proteasome inhibitor (PI) bortezomib, have led to improved prognosis of MM [1]. Before the introduction of alkylating agents Copyright: © 2021 by the authors. in MM treatment, the median survival time of symptomatic patients was <1 year, and the Licensee MDPI, Basel, Switzerland. introduction of melphalan in the 1960s resulted in improved survival [3,4]. High-dose This article is an open access article melphalan (HDM) followed by autologous stem cell transplantation (ASCT) has become a distributed under the terms and standard of care for younger patients after bortezomib-based induction regimens [5,6]. In conditions of the Creative Commons addition, the introduction of novel agents, particularly bortezomib combined with lenalido- Attribution (CC BY) license (https:// mide plus dexamethasone, has improved the outcome of patients who are ineligible for creativecommons.org/licenses/by/ ASCT [7]. Recently, carfilzomib [8], pomalidomide [9], panobinostat [10], ixazomib [11], 4.0/). Cancers 2021, 13, 504. https://doi.org/10.3390/cancers13030504 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 2 of 22 of patients who are ineligible for ASCT [7]. Recently, carfilzomib [8], pomalidomide [9], Cancers 2021, 13, 504 panobinostat [10], ixazomib [11], elotuzumab [12], daratumumab [13], isatuximab2 of 23 [14], and selinexor [15] have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed MM and promise to improve outcomes. Currently, numerous combination therapies are available and include immunomodulatory drugs, PIs, histone elotuzumab [12], daratumumab [13], isatuximab [14], and selinexor [15] have been ap- proveddeacetylase by the inhibitors, Food and Drug and Administrationmonoclonal antibodies. (FDA) for the However, treatment ofMM relapsed remains MM an and incurable promisedisease, toand improve new therapeutic outcomes. Currently, strategies numerous are still needed combination [1]. therapies are available and includeMM cells immunomodulatory present genomic drugs, instability PIs, histone [16], deacetylase whose inhibitors, molecular and monoclonalbasis is not fully antibodies.understood. However, Recently, MM it remainshas been an reported incurable that disease, the andDNA new damage therapeutic response strategies (DDR) may areinfluence still needed genomic [1]. changes in MM [17–20]. An abnormal DNA repair function may provideMM cellsan alternative present genomic explanation instability for [16 aneuploidy], whose molecular and chromosomal basis is not fully rearrangements. under- stood.Furthermore, Recently, the it has tumor been microenvironment reported that the DNA may damage be mutagenic response (DDR)and constitute may influence a significant genomic changes in MM [17–20]. An abnormal DNA repair function may provide an alter- source of genetic instability, affecting genomic stability and tumor resistance to treatment native explanation for aneuploidy and chromosomal rearrangements. Furthermore, the tumor(Figure microenvironment 1) [21–23]. This mayreview be mutagenicprovides an and overview constitute of a significantthe DDR, sourcewith a of special genetic focus on instability,its function affecting on MM. genomic We stabilitywill also and discuss tumor resistance the role to of treatment DNA repair (Figure 1in)[ regulating21–23]. the Thismetabolism review provides and progression an overview of ofMM the cells. DDR, with a special focus on its function on MM. We will also discuss the role of DNA repair in regulating the metabolism and progression of MM cells. FigureFigure 1. 1. DNADNA damagedamage response response in multiplein multiple myeloma myeloma and the and tumor th microenvironment.e tumor microenvironment. Tumor microenvironment Tumor microenvironment factors, factors,such as such chemotherapeutic as chemotherapeutic agents, inflammation, agents, inflammation, ROS, cytokines, ROS, genotoxic cytokines, stress, genotoxic and hypoxia, stress, influence and hypoxia, the DNA influence damage the DNA damageresponse response in MM cells.in MM The cells. DNA The damage DNA response damage affects response disease affe progressioncts disease andprogression drug resistance. and drug ROS, resistance. reactive oxygen ROS, reactive oxygenspecies; species; OC, osteoclast; OC, osteoclast; BMSC, bone BMSC, marrow bo stromalne marrow cell; MMstromal Cell, multiplecell; MM myeloma Cell, multiple cell; SSBs, myeloma single-strand cell; breaks; SSBs, DSBs,single-strand breaks;double-strand DSBs, double-strand breaks. breaks. 2. Genomic Damage Damage Genomic stability is important for ensuring the inheritance of correct genetic infor- Genomic stability is important for ensuring the inheritance of correct genetic mation. The occurrence of genomic instability can result in harmful consequences, which mightinformation. lead tosevere The occurrence diseases, such of asgenomic cancers. instability Endogenous can and result exogenous in harmful environmental consequences, factorswhich canmight act aslead DNA-damaging to severe diseases, agents, causing such genetic as cancers. mutations Endogenous [23,24]. Endogenous and exogenous factorsenvironmental include natural factors metabolic can act byproducts, as DNA-damaging such as those agents, resulting causing from oxidation, genetic alky- mutations lation,[23,24]. hydrolysis, Endogenous and mismatchfactors include of DNA natural bases, whilemetabolic exogenous byproducts, factors includesuch as ionizing those resulting radiation,from oxidation, ultraviolet alkylation, (UV) radiation, hydrolysis, and various and mismatch chemical agents of DNA [24, 25bases,]. These while factors exogenous havefactors been include associated ionizing with theradiation, etiology ultraviolet of human cancer (UV) [radiation,23,24,26], with and thevarious induced chemical DNA agents damage[24,25]. beingThese an factors important have first been step associated in the process with of the carcinogenesis. etiology of human Noteworthy, cancer each [23,24,26], human cell is estimated to endure approximately 70,000 DNA damage lesions per day [24]. with the induced DNA damage being an important first step in the process of Damaged DNA that is not properly repaired can then lead to genomic instability, apoptosis, carcinogenesis. Noteworthy, each human cell is estimated to endure approximately 70,000 Cancers 2021, 13, 504 3 of 23 or senescence [27]. Therefore, DNA repair systems are important to protect DNA integrity, as the resolution of DNA damage lesions
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