Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Plasma cells are prone to produce large amounts of immunoglobulins causing the production of intracellular ROS. Although adapted to high level of ROS, MM cells die when exposed to drugs increasing ROS production either directly or by inhibiting antioxidant enzymes. In this review, we discuss the efficacy of ROS-generating drugs for inducing MM cell death and counteracting acquired drug resistance specifically toward proteasome inhibitors.

Section: Metabolism Rewiringmentioning

confidence: 99%

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

Caillot

Dakik

Mazurier

et al. 2021

“…MYC has been described as a protooncogene involved in many cancers, including leukemia and lymphoma [5][6][7]. In MM, it is known that aberrant expression of MYC is due to recurrent chromosomal alterations [8] and previous studies have demonstrated that its expression is involved in MM progression from early stages of plasma cell dyscrasias, including monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM), to MM [9]. Several authors have reported that MYC deregulation is involved in disease progression and has been related with poor progression-free survival in MM patients [10].…”

Section: Introductionmentioning

confidence: 99%

Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma

Ortiz-Ruiz

Ruiz‐Heredia

Morales

et al. 2021

Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitochondrial inhibitor, tigecycline, to overcome MM proliferation. COXII expression, COX activity, mitochondrial mass, and mitochondrial membrane potential demonstrated a progressive increase of mitochondrial features as the disease progresses. In vitro and in vivo therapeutic targeting using the mitochondrial inhibitor tigecycline showed promising efficacy and cytotoxicity in monotherapy and combination with the MM frontline treatment bortezomib. Overall, our findings demonstrate how mitochondrial activity emerges in MM transformation and disease progression and the efficacy of therapies targeting these novel vulnerabilities.

“…Here, we report that elevated mtDNACN, which reflects the abundance of mitochondria, is an additional feature of MM. Our data provide evidence that the malignant transformation of myeloma cells is coupled to the activation of mitochondrial biogenesis, resulting in increased mtDNA levels [3][4][5] and mtDNACN changes [6,8,9]. Indeed, mtDNA can define early and late tumor progression in MM [12].…”

Section: Discussionmentioning

confidence: 67%

“…Mitochondria appear to be essential for tumor formation and growth [6], and dysfunction in mitochondrial processes affects the electron transport chain and promotes tumor metastasis [7]. Indeed, cancer is characterized by altered energy metabolism involving not only genetic alterations in nuclear DNA, but also mtDNA mutations and changes in mtDNACN [6,8,9]. A recent comprehensive study of the mtDNACN in many cancer types revealed that the majority show changes in mtDNA content when compared with adjacent healthy tissue [9], and also that the mtDNACN is significantly associated with patient survival.…”

Section: Introductionmentioning

confidence: 99%

Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma

Ruiz‐Heredia

Ortiz-Ruiz

Samur

et al. 2021

Many studies over the last 20 years have investigated the role of mitochondrial DNA (mtDNA) alterations in carcinogenesis. However, the status of the mtDNACN in MM and its implication in the pathogenesis of the disease remains unclear. We examined changes in plasma cell mtDNACN across different stages of MM by applying RT-PCR and high-throughput sequencing analysis. We observed a significant increase in the average mtDNACN in myeloma cells compared with healthy plasma cells (157 vs. 40 copies; p = 0.02). We also found an increase in mtDNACN in SMM and newly diagnosed MM (NDMM) paired samples and in consecutive relapses in the same patient. Survival analysis revealed the negative impact of a high mtDNACN in progression-free survival in NDMM (p = 0.005). Additionally, we confirmed the higher expression of mitochondrial biogenesis regulator genes in myeloma cells than in healthy plasma cells and we detected single nucleotide variants in several genes involved in mtDNA replication. Finally, we found that there was molecular similarity between “rapidly-progressing SMM” and MM regarding mtDNACN. Our data provide evidence that malignant transformation of myeloma cells involves the activation of mitochondrial biogenesis, resulting in increased mtDNA levels, and highlights vulnerabilities and potential therapeutic targets in the treatment of MM. Accordingly, mtDNACN tracking might guide clinical decision-making and management of complex entities such as high-risk SMM.