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Cytogenetics and Molecular Genetics

Downregulation of specific miRNAs in hyperdiploid multiple myeloma mimics the oncogenic effect of IgH translocations occurring in the non-hyperdiploid subtype

Leukemia volume 27, pages 925–931 (2013)Cite this article

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Abstract

Currently, multiple myeloma (MM) patients are broadly grouped into a non-hyperdiploid (nh-MM) group, highly enriched for IgH translocations, or into a hyperdiploid (h-MM) group, which is typically characterized by trisomies of some odd-numbered chromosomes. We compared the micro RNA (miRNA) expression profiles of these two groups and we identified 16 miRNAs that were downregulated in the h-MM group, relative to the nh-MM group. We found that target genes of the most differentially expressed miRNAs are directly involved in the pathogenesis of MM; specifically, the inhibition of hsa-miR-425, hsa-miR-152 and hsa-miR-24, which are all downregulated in h-MM, leads to the overexpression of CCND1, TACC3, MAFB, FGFR3 and MYC, which are the also the oncogenes upregulated by the most frequent IgH chromosomal translocations occurring in nh-MM. Importantly, we showed that the downregulation of these specific miRNAs and the upregulation of their targets also occur simultaneously in primary cases of h-MM. These data provide further evidence on the unifying role of cyclin D pathways deregulation as the key mechanism involved in the development of both groups of MM. Finally, they establish the importance of miRNA deregulation in the context of MM, thereby opening up the potential for future therapeutic approaches based on this molecular mechanism.

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Acknowledgements

This work was partially funded by INTRASALUD PI 08-0440 (to JCC), Fondo de Investigaciones Sanitarias (Spain). We thank the staff of the Molecular Cytogenetics Group at the CNIO (Madrid, Spain), the Department of Genetics, University of Navarra (Pamplona, Spain) and the Division of Hematology–Oncology, Mayo Clinic (Scottsdale, Arizona, USA) for their support in the molecular cytogenetic characterization of the samples.

Author contributions

JCC designed the study and wrote the paper; AR-M, BF, TH and XA performed the experiments; GG-L, BIF, AR-M, SA, SR-P and JCC analyzed the data; FP, MJC, JM and RF provided key reagents and materials.

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Authors and Affiliations

  1. Molecular Cytogenetics Group, Human Cancer Genetics Program, Centro Nacional Investigaciones Oncológicas (CNIO), Calle Melchor Fernández Almagro 3, Madrid, Spain

    A Rio-Machin, B I Ferreira, S Alvarez, S Rodriguez-Perales & J C Cigudosa

  2. Centro de Investigaciones de Enfermedades Raras (CIBERER), Madrid, Spain

    A Rio-Machin, B I Ferreira, S Alvarez, S Rodriguez-Perales & J C Cigudosa

  3. Division of Hematology–Oncology, Mayo Clinic, Scottsdale, AZ, USA

    T Henry & R Fonseca

  4. Bioinformatics Unit, Centro Nacional Investigaciones Oncologicas (CNIO), Calle Melchor Fernández Almagro 3, Madrid, Spain

    G Gómez-López

  5. Division of Cancer and Area of Cell Therapy and Hematology Service, Foundation for Applied Medical Research, Clínica Universitaria, Universidad de Navarra, Pamplona, Spain

    X Agirre & F Prosper

  6. Department of Genetics, University of Navarra, Campus Universitario, Pamplona, Spain

    M J Calasanz

  7. Hematology Service, Hospital Universitario 12 de Octubre, Madrid, Spain

    J Martínez

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  1. A Rio-Machin
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Correspondence to J C Cigudosa.

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Competing interests

Relevant to this work Dr Fonseca holds a patent for the prognostication of MM based on the genetic categorization of the disease. Not relevant to this work, Dr Fonseca has received consulting fees from Medtronic, Otsuka, Celgene, Genzyme, BMS and AMGEN. He has also received funding for research from Cylene and Onyx. The remaining authors declare no conflicts of interest.

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Rio-Machin, A., Ferreira, B., Henry, T. et al. Downregulation of specific miRNAs in hyperdiploid multiple myeloma mimics the oncogenic effect of IgH translocations occurring in the non-hyperdiploid subtype. Leukemia 27, 925–931 (2013). https://doi.org/10.1038/leu.2012.302

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