Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease.
Although multiple myeloma (MM) is a unique entity, a marked heterogeneity is actually observed among the patients, which has been first related to immunoglobulin (Ig) types and light chain subtypes and more recently to chromosomal abnormalities. To further investigate this genetic heterogeneity, we analyzed gene expression profiles of 92 primary tumors according to their Ig types and light chain subtypes with DNA microarrays. Several clusters of genes involved in various biologic functions such as immune response, cell cycle control, signaling, apoptosis, cell adhesion, and structure significantly discriminated IgA- from IgG-MM. Genes associated with inhibition of differentiation and apoptosis induction were up-regulated while genes associated with immune response, cell cycle control, and apoptosis were down-regulated in IgA-MM. According to the expression of the 61 most discriminating genes, BJ-MM represented a separate subgroup that did not express either the genes characteristic of IgG-MM or those of IgA-MM at a high level. This suggests that transcriptional programs associated to the switch could be maintained up to plasma cell differentiation. Several genes whose products are known to stimulate bone remodeling discriminate between kappa- and lambda-MM. One of these genes, Mip-1alpha, was overexpressed in the kappa subgroup. In addition, we established a strong association (P =.0001) between kappa subgroup expressing high levels of Mip-1alpha and active myeloma bone disease. This study shows that DNA microarrays enable us to perform a molecular dissection of the bioclinical diversity of MM and provide new molecular tools to investigate the pathogenesis of malignant plasma cells.
Magrangeas
Florence
F
INSERM U463, Department of Clinical Hematology, University Hospital, Nantes, France.
Nasser
Valéry
V
Avet-Loiseau
Hervé
H
Loriod
Béatrice
B
Decaux
Olivier
O
Granjeaud
Samuel
S
Bertucci
François
F
Birnbaum
Daniel
D
Nguyen
Catherine
C
Harousseau
Jean-Luc
JL
Bataille
Régis
R
Houlgatte
Rémi
R
Minvielle
Stéphane
S
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D005802:Genes, MHC Class II; D018816:Genes, cdc; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D019402:Macrophage Inflammatory Proteins