title: Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma.
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.
authors.affiliation: Department of Haematology/Oncology, Mayo Clinic Comprehensive Cancer Center, Scottsdale, AZ, USA. mdccwj@nus.edu.sg
authors.forename: W-J
authors.initials: WJ
authors.lastname: Chng
authors.forename: G F
authors.initials: GF
authors.lastname: Huang
authors.forename: T H
authors.initials: TH
authors.lastname: Chung
authors.forename: S B
authors.initials: SB
authors.lastname: Ng
authors.forename: N
authors.initials: N
authors.lastname: Gonzalez-Paz
authors.forename: T
authors.initials: T
authors.lastname: Troska-Price
authors.forename: G
authors.initials: G
authors.lastname: Mulligan
authors.forename: M
authors.initials: M
authors.lastname: Chesi
authors.forename: P L
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: R
authors.initials: R
authors.lastname: Fonseca
mesh_terms: D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002453:Cell Cycle / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics* / Q000473:pathology; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000627:therapeutic use; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics
chemical_list: D001897:Boronic Acids; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D000069286:Bortezomib; D018631:ras Proteins