Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma

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Ruiz Heredia, Yanira and Ortiz Ruiz, Alejandra and Samur, Mehmet K. and Garrido, Vanesa and Rufian, Laura and Sanchez, Ricardo and Aguilar-Garrido, Pedro and Barrio, Santiago and Martín, Miguel A. and Bolli, Niccolò and Tai, Yu-Tzu and Szalat, Raphaël and Fulciniti, Mariateresa and Munshi, Nikhil and Martínez López, Joaquín and Linares Gómez, María and Gallardo, Miguel (2021) Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma. Cancers, 13 (13). p. 3189. ISSN 2072-6694

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Official URL: https://doi.org/10.3390/cancers13133189




Abstract

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.


Item Type:Article
Uncontrolled Keywords:multiple myeloma; smoldering MM; mitochondria DNA copy number; NGS
Subjects:Medical sciences > Medicine > Medical genetics
Medical sciences > Biology > Genetics
ID Code:70886
Deposited On:01 Mar 2022 17:10
Last Modified:02 Mar 2022 09:37

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