Transcriptional features of multiple myeloma patients with chromosome IQ gain

Introduction. Abnormalities of chromosome 1 are among the most frequentchromosomal alterations in MM (45% of patients). The long armof chromosome 1 is associated with amplification (1q/gain) that canoccur as isochromosomes, duplications or jumping translocations.1q/gain MM patients are characterized by complex karyotypes andaggressive disease, and their number increases as the condition goesfrom smoldering to overt MM, suggesting that these regions containcritical genes for disease progression. These findings along with the limitedinformation concerning specific transcriptional profiles, promptedus to molecularly characterize 1q/gain MMs by FISH and microarrayanalyses. Methods. Purified plasma cells from 77 MMs at diagnosis werecharacterized by FISH for the presence of 11 polisomy, the most recurrentIGH translocations, ploidy status, chromosome 13 deletion, and byglobal gene expression profiling using the Affymetrix U133A arrays.Assessment of 1q/gain by FISH was performed by using three BACclones specific for the BCL9 (1q21.1), CKS1B (1q22) and ARF1 (1q42.13)loci, and setting the threshold as 10%. Results. 1q/gain was identified in40/77 (51.9%) patients; three (75%) or four (12.5%) signals of all the 1qprobes were found in 35 patients and, in the remaining five samples(12.5%), the probes mapping to 1q21 and 1q22 showed more signalsthan that mapping to 1q42. 1q/gain was observed in the majority ofpurified plasma cells (median 96%) in all but three patients (range 12-20%). 1q extra copies significantly correlated with chromosome 13 deletion(p<10-4), and the absence of chromosome 11 polisomy (p=0.038),but not with ploidy status (p=0.0971). The differential expression of 61genes (mainly localized on chromosome 1q12-1q44) distinguishes MMpatients with or without 1q/gain. Functional analysis of the identifiedgenes revealed their involvement in energy production pathways, intracellularprotein transport, and endoplasmic reticulum-stress inducedresponses. The transcriptional fingerprint was robustly validated on apublicly available gene expression dataset, with a global classificationrate of 85.2% for the independent cohort of MM cases. Discussion. Thesedata improve our knowledge concerning the specific genes/pathwaysderegulated by 1q abnormalities, and provide a promising focus for furtherstudies aimed at defining new therapeutic strategies in MM.