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.