Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis.
To define specific pathways important in the multistep transformation process of normal plasma cells (PCs) to monoclonal gammopathy of uncertain significance (MGUS) and multiple myeloma (MM), we have applied microarray analysis to PCs from 5 healthy donors (N), 7 patients with MGUS, and 24 patients with newly diagnosed MM. Unsupervised hierarchical clustering using 125 genes with a large variation across all samples defined 2 groups: N and MGUS/MM. Supervised analysis identified 263 genes differentially expressed between N and MGUS and 380 genes differentially expressed between N and MM, 197 of which were also differentially regulated between N and MGUS. Only 74 genes were differentially expressed between MGUS and MM samples, indicating that the differences between MGUS and MM are smaller than those between N and MM or N and MGUS. Differentially expressed genes included oncogenes/tumor-suppressor genes (LAF4, RB1, and disabled homolog 2), cell-signaling genes (RAS family members, B-cell signaling and NF-kappaB genes), DNA-binding and transcription-factor genes (XBP1, zinc finger proteins, forkhead box, and ring finger proteins), and developmental genes (WNT and SHH pathways). Understanding the molecular pathogenesis of MM by gene expression profiling has demonstrated sequential genetic changes from N to malignant PCs and highlighted important pathways involved in the transformation of MGUS to MM.
Davies
Faith E
FE
Academic Unit of Haematology and Oncology, Algernon Firth Bldg, School of Medicine, University of Leeds, Leeds, United Kingdom. faith@egu.leeds.ac.uk
Dring
Ann M
AM
Li
Cheng
C
Rawstron
Andrew C
AC
Shammas
Masood A
MA
O'Connor
Sheila M
SM
Fenton
James A L
JA
Hideshima
Teru
T
Chauhan
Dharminder
D
Tai
Isabella T
IT
Robinson
Elizabeth
E
Auclair
Daniel
D
Rees
Karen
K
Gonzalez
David
D
Ashcroft
A John
AJ
Dasgupta
Ranjit
R
Mitsiades
Constantine
C
Mitsiades
Nicholas
N
Chen
Lan B
LB
Wong
Wing H
WH
Munshi
Nikhil C
NC
Morgan
Gareth J
GJ
Anderson
Kenneth C
KC
D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D010265:Paraproteinemias / Q000235:genetics / Q000473:pathology*; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D013382:Subtraction Technique; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D014157:Transcription Factors