Molecular classification of light chain (AL) amyloidosis by gene expression profiling

Immunoglobulin light chain amyloidosis (AL) is characterized by a clonal expansion of plasma cells within the bone marrow. Gene expression analysis was used to identify a unique molecular profile for AL using enriched plasma cells (CD138+) from the bone marrow of 24 AL and 28 MM patients. Class prediction analysis revealed 29 genes that could distinguish between AL and MM patients with an observed accuracy of 90% and estimated accuracy of 81%. A subset of 12 genes that included TNFRSF7, SDF-1, JUN, PSMA2, DEFA1, NDUFA4, PGK1 and TXN improved the estimated and observed accuracy of classification to 92%. Functional analysis using a novel network mapping software, identified 1051 Focus Genes. Forty-seven genes were further analyzed for their significance to the biology of AL. Notably, these included 8 of the 12 genes as well as CCND1, CDK4, Rb1, BTRC among cell cycle genes, oncogenes-MYC, JUN and p53, XRCC5/XRCC4 and E2A in DNA repair and Ig rearrangement. Importantly, genes deregulated with respect to protein processing and folding included A2M, PSEN1 and 2, APP, UCHL1, SERPINA1 and CASP3. This study provides new insight into the molecular profile of clonal plasma cells and its functional relevance in the pathogenesis of light chain amyloidosis.