title: Genome-wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles.
abstract: Primary plasma cell leukemia (pPCL) is a rare, yet aggressive form of de novo plasma cell tumor, distinct from secondary PCL (sPCL) which represents a leukemic transformation of pre-existing multiple myeloma (MM). Herein, we performed a comprehensive molecular analysis of a prospective series of pPCLs by means of FISH, single nucleotide polymorphism (SNP) array and gene expression profiling (GEP). IGH@ translocations were identified in 87% of pPCL cases, with prevalence of t(11;14) (40%) and t(14;16) (30.5%), whereas the most frequent numerical alterations involved 1p (38%), 1q (48%), 6q (29%), 8p (42%), 13q (74%), 14q (71%), 16q (53%), and 17p (35%). We identified a minimal biallelic deletion (1.5 Mb) in 8p21.2 encompassing the PPP2R2A gene, belonging to a family of putative tumor suppressors and found to be significantly down-regulated in deleted cases. Mutations of TP53 were identified in four cases, all but one associated with a monoallelic deletion of the gene, whereas activating mutations of the BRAF oncogene occurred in one case and were absent in N- and K-RAS. To evaluate the influence of allelic imbalances in transcriptional expression we performed an integrated genomic analysis with GEP data, showing a significant dosage effect of genes involved in transcription, translation, methyltransferase activity, apoptosis as well as Wnt and NF-kB signaling pathways. Overall, we provide a compendium of genomic alterations in a prospective series of pPCLs which may contribute to improve our understanding of the pathogenesis of this aggressive form of plasma cell dyscrasia and the mechanisms of tumor progression in MM.
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mosca
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Musto
authors.forename: Katia
authors.initials: K
authors.lastname: Todoerti
authors.forename: Marzia
authors.initials: M
authors.lastname: Barbieri
authors.forename: Luca
authors.initials: L
authors.lastname: Agnelli
authors.forename: Sonia
authors.initials: S
authors.lastname: Fabris
authors.forename: Giacomo
authors.initials: G
authors.lastname: Tuana
authors.forename: Marta
authors.initials: M
authors.lastname: Lionetti
authors.forename: Eleonora
authors.initials: E
authors.lastname: Bonaparte
authors.forename: Silvia Maria
authors.initials: SM
authors.lastname: Sirchia
authors.forename: Vitina
authors.initials: V
authors.lastname: Grieco
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bianchino
authors.forename: Fiorella
authors.initials: F
authors.lastname: D'Auria
authors.forename: Teodora
authors.initials: T
authors.lastname: Statuto
authors.forename: Carmela
authors.initials: C
authors.lastname: Mazzoccoli
authors.forename: Luciana
authors.initials: L
authors.lastname: De Luca
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.forename: Fortunato
authors.initials: F
authors.lastname: Morabito
authors.forename: Massimo
authors.initials: M
authors.lastname: Offidani
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.forename: Antonietta
authors.initials: A
authors.lastname: Falcone
authors.forename: Tommaso
authors.initials: T
authors.lastname: Caravita
authors.forename: Paola
authors.initials: P
authors.lastname: Omedè
authors.forename: Mario
authors.initials: M
authors.lastname: Boccadoro
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D055106:Genome-Wide Association Study; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007952:Leukemia, Plasma Cell / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; D014157:Transcription Factors