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PMID: 21468039 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Leukemia ·Vol. 25 ·No. 6 ·2011-06-00 ·Pages 1026-35

Chng WJ, Huang GF, Chung TH, Ng SB, Gonzalez-Paz N, Troska-Price T, Mulligan G, Chesi M, Bergsagel PL, Fonseca R

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.

MeSH Terms
Boronic Acids/therapeutic use Bortezomib Cell Cycle/genetics Cell Transformation, Neoplastic/genetics Gene Expression Profiling Humans Monoclonal Gammopathy of Undetermined Significance/genetics,pathology Multiple Myeloma/genetics,pathology Mutation Proto-Oncogene Proteins c-myc/genetics,metabolism Pyrazines/therapeutic use Survival Rate ras Proteins/genetics
Chemicals
Boronic Acids MYC protein, human Proto-Oncogene Proteins c-myc Pyrazines Bortezomib ras Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Chng W-J
Department of Haematology/Oncology, Mayo Clinic Comprehensive Cancer Center, Scottsdale, AZ, USA. [email protected]
Huang G F
Chung T H
Ng S B
Gonzalez-Paz N
Troska-Price T
Mulligan G
Chesi M
Bergsagel P L
Fonseca R
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Article Info
Journal
Leukemia
Abbr.
Leukemia
ISSN
1476-5551
DOI
10.1038/leu.2011.53
Email
[email protected]
Published
2011-06-00
Epub
2011-00-05
Pages
1026-35
Language
English
Region
England
NLM ID
8704895
PMCID
PMC3432644
Subset
IM
Grants
NCI NIH HHS · R01 CA083724 · United States
NCI NIH HHS · R01 CA136671 · United States
NCI NIH HHS · P01 CA62242 · United States
NCI NIH HHS · R01 CA136671-04 · United States
NCI NIH HHS · P01 CA062242 · United States
NCI NIH HHS · R01 CA83724-01 · United States
NCI NIH HHS · N01 CA015083 · United States
NIA NIH HHS · R01 AG020686-08 · United States
NIA NIH HHS · R01 AG020686 · United States
NCI NIH HHS · P50 CA100707-01 · United States
NCI NIH HHS · CA015083 · United States
NCI NIH HHS · P30 CA015083 · United States
NCI NIH HHS · R01 CA133966-03 · United States
NCI NIH HHS · P50 CA100707 · United States
NCI NIH HHS · R01 CA133966 · United States
External Links
PubMed source DOI: 10.1038/leu.2011.53 PMC Full Text View journal details
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