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Myeloma

Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma

Leukemia volume 25, pages 1026–1035 (2011)Cite this article

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Abstract

Events mediating transformation from the pre-malignant monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are unknown. We analyzed gene expression data sets generated on the Affymetrix U133 platform from 22 MGUS and 101 MM patients using gene-set enrichment analysis. Genes overexpressed in MM were enriched for cell cycle, proliferation and MYC activation gene sets. Upon dissecting the relationship between MYC and cell-cycle gene sets, we identified and validated an MYC activation signature dissociated from proliferation. Applying this signature, MYC is activated in 67% of myeloma, but not in MGUS. This was further confirmed by immunohistochemistry (IHC) using membrane CD138 and nuclear MYC double staining. We also showed that almost all tumors with RAS mutations expressed the MYC activation signature, and multiple mechanisms may be involved in activating MYC. MYC activation, whether assessed by gene-expression signature or IHC, is associated with hyperdiploid MM and shorter survival even in tumors that are not proliferative. Bortezomib treatment is able to overcome the survival disadvantage in patients with MYC activation.

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Acknowledgements

We express our gratitude to Ms Choo Shoa Nian from department of pathology, National University of Singapore, for performing immunohistochemistry. We also thank Prof Chi Van Dang, from John Hopkins, for his helpful suggestions and sharing the gene expression data for the P493-6 cell line model. WJC is supported by NMRC Clinician Scientist Investigator award. This work is partly supported by Singapore Cancer Syndicate Grant (SCS-GRN102), and the Singapore National research Foundation and the Ministry of Education under the Research Center of Excellence Programme. RF is a Clinical Investigator of the Damon Runyon Cancer Research Fund. This work is supported by grants R01 CA83724-01, SPORE P50, CA100707-01and P01 CA62242 from the National Cancer Institute. Dr Fonseca is also supported by the grant CA015083 from the National Cancer Institute.

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Authors and Affiliations

  1. Department of Haematology/Oncology, Mayo Clinic Comprehensive Cancer Center, Scottsdale, AZ, USA

    W-J Chng, M Chesi, P L Bergsagel & R Fonseca

  2. Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, National University of Singapore, Singapore

    W-J Chng & G F Huang

  3. Cancer Science Institute Singapore, National University of Singapore, Singapore

    W-J Chng & T H Chung

  4. Department of Pathology, National University of Singapore, Singapore

    S B Ng

  5. Department of Haematology, Mayo Clinic, Rochester, MN, USA

    N Gonzalez-Paz & T Troska-Price

  6. Translational Medicine, Millenium Pharmaceuticals, Boston, MA, USA

    G Mulligan

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  1. W-J Chng
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Correspondence to W-J Chng.

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Competing interests

Chng W-J has received honorariums from Janssen Cilag. Mulligan G is an employee of Millenium Pharmaceuticals, which makes Bortezomib.

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Author Contributions

Chng W-J, designed study, performed analysis and wrote paper; Huang GF, performed gene expression analysis; Chung TH, performed statistical analysis; Ng SB, performed IHC analysis; Gonzalez-Paz N, performed RAS mutation analysis; Price-Troska T, performed RAS mutation analysis; Mulligan G, provided Bortezomib GEP data and analysis; Chesi M, designed study and approved final manuscript; Bergsagel PL, designed study and approved final manuscript; Fonseca R, designed study, provided tissue microarrays and approved final manuscript.

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Chng, WJ., Huang, G., Chung, T. et al. Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia 25, 1026–1035 (2011). https://doi.org/10.1038/leu.2011.53

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