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.