Pathogenetic and prognostic implications of increased mitochondrial content in multiple myeloma

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number3189
JournalCancers
Volume13
Issue number13
DOIs
Publication statusPublished - Jul 1 2021

Keywords

  • Mitochondria DNA copy number
  • Multiple myeloma
  • NGS
  • Smoldering MM

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Pathogenetic and prognostic implications of increased mitochondrial content in multiple myeloma'. Together they form a unique fingerprint.

Cite this