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

• Published in: Leukemia Vol. 25; no. 6; pp. 1026 - 1035
• Main Authors: Chng, W-J, Huang, G F, Chung, T H, Ng, S B, Gonzalez-Paz, N, Troska-Price, T, Mulligan, G, Chesi, M, Bergsagel, P L, Fonseca, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2011; Nature Publishing Group
• Subjects: 631/208/191/2018; 692/699/249/1573; 692/699/67/1059/99; 692/699/67/1990/804; Antibodies; Benign monoclonal gammopathy; Biological and medical sciences; Boronic Acids - therapeutic use; Bortezomib; Cancer Research; Cell cycle; Cell Cycle - genetics; Cell Transformation, Neoplastic - genetics; Cloning; Critical Care Medicine; Diagnosis; Diagnostic immunohistochemistry; Gene expression; Gene Expression Profiling; Genetic aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunohistochemistry; Immunopathology; Intensive; Internal Medicine; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical prognosis; Medical sciences; Medicine; Medicine & Public Health; Monoclonal Gammopathy of Undetermined Significance - genetics; Monoclonal Gammopathy of Undetermined Significance - pathology; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Mutation; Myc protein; Oncology; original-article; Patients; Phosphatase; Polymers; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Pyrazines - therapeutic use; ras Proteins - genetics; Survival; Survival Rate; Tumors; Singapore; United States > US; myeloma; bortezomib; MGUS; MYC; hyperdiploid; Antineoplastic agent; Immunopathology; Polyploidy; Bortezomib; Hematology; Early stage; B cell neoplasm; Malignant hemopathy; Lymphoid neoplasm; Myeloma; Monoclonal gammopathy of undetermined significance; Immunoglobulinopathy; Analog; Proteasome inhibitor; Lymphoproliferative syndrome; C-Onc gene; Dipeptides; myc Gene; Protooncogene; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.53

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.