Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma
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 stag...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/13/3189 |
| _version_ | 1797528654462320640 |
|---|---|
| author | Yanira Ruiz-Heredia Alejandra Ortiz-Ruiz Mehmet K. Samur Vanesa Garrido Laura Rufian Ricardo Sanchez Pedro Aguilar-Garrido Santiago Barrio Miguel A. Martín Niccolò Bolli Yu-Tzu Tai Raphaël Szalat Mariateresa Fulciniti Nikhil Munshi Joaquín Martínez-López María Linares Miguel Gallardo |
| author_facet | Yanira Ruiz-Heredia Alejandra Ortiz-Ruiz Mehmet K. Samur Vanesa Garrido Laura Rufian Ricardo Sanchez Pedro Aguilar-Garrido Santiago Barrio Miguel A. Martín Niccolò Bolli Yu-Tzu Tai Raphaël Szalat Mariateresa Fulciniti Nikhil Munshi Joaquín Martínez-López María Linares Miguel Gallardo |
| author_sort | Yanira Ruiz-Heredia |
| collection | DOAJ |
| description | 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; <i>p</i> = 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 (<i>p</i> = 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. |
| first_indexed | 2024-03-10T10:02:25Z |
| format | Article |
| id | doaj.art-2d87ff73e0fc4a788283cc2f4a7faf28 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T10:02:25Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2d87ff73e0fc4a788283cc2f4a7faf282023-11-22T01:49:52ZengMDPI AGCancers2072-66942021-06-011313318910.3390/cancers13133189Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple MyelomaYanira Ruiz-Heredia0Alejandra Ortiz-Ruiz1Mehmet K. Samur2Vanesa Garrido3Laura Rufian4Ricardo Sanchez5Pedro Aguilar-Garrido6Santiago Barrio7Miguel A. Martín8Niccolò Bolli9Yu-Tzu Tai10Raphaël Szalat11Mariateresa Fulciniti12Nikhil Munshi13Joaquín Martínez-López14María Linares15Miguel Gallardo16H12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainH12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainDana-Farber Cancer Institute, 450 Brookline Avenue, M230 Boston, MA 02215, USAH12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainHematology Department, Hospital Universitario 12 de Octubre, 28041 Madrid, SpainH12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainH12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainH12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainInstituto de Investigación, Hospital Universitario 12 de Octubre, 28041 Madrid, SpainHematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, ItalyDana-Farber Cancer Institute, 450 Brookline Avenue, M230 Boston, MA 02215, USADana-Farber Cancer Institute, 450 Brookline Avenue, M230 Boston, MA 02215, USADana-Farber Cancer Institute, 450 Brookline Avenue, M230 Boston, MA 02215, USADana-Farber Cancer Institute, 450 Brookline Avenue, M230 Boston, MA 02215, USAH12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainH12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainH12O-CNIO Hematological Malignancies Clinical Research Unit, CNIO, 28029 Madrid, SpainMany 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; <i>p</i> = 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 (<i>p</i> = 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.https://www.mdpi.com/2072-6694/13/13/3189multiple myelomasmoldering MMmitochondria DNA copy numberNGS |
| spellingShingle | Yanira Ruiz-Heredia Alejandra Ortiz-Ruiz Mehmet K. Samur Vanesa Garrido Laura Rufian Ricardo Sanchez Pedro Aguilar-Garrido Santiago Barrio Miguel A. Martín Niccolò Bolli Yu-Tzu Tai Raphaël Szalat Mariateresa Fulciniti Nikhil Munshi Joaquín Martínez-López María Linares Miguel Gallardo Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma Cancers multiple myeloma smoldering MM mitochondria DNA copy number NGS |
| title | Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma |
| title_full | Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma |
| title_fullStr | Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma |
| title_full_unstemmed | Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma |
| title_short | Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma |
| title_sort | pathogenetic and prognostic implications of increased mitochondrial content in multiple myeloma |
| topic | multiple myeloma smoldering MM mitochondria DNA copy number NGS |
| url | https://www.mdpi.com/2072-6694/13/13/3189 |
| work_keys_str_mv | AT yaniraruizheredia pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT alejandraortizruiz pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT mehmetksamur pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT vanesagarrido pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT laurarufian pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT ricardosanchez pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT pedroaguilargarrido pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT santiagobarrio pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT miguelamartin pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT niccolobolli pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT yutzutai pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT raphaelszalat pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT mariateresafulciniti pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT nikhilmunshi pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT joaquinmartinezlopez pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT marialinares pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma AT miguelgallardo pathogeneticandprognosticimplicationsofincreasedmitochondrialcontentinmultiplemyeloma |