Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma.
Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of the alpha-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.
Mattioli
Michela
M
Laboratorio di Ematologia Sperimentale e Genetica Molecolare and U.O. Ematologia 1, Dipartimento di Scienze Mediche, Università degli Studi di Milano, Ospedale Maggiore IRCCS, Milano, Italy.
Agnelli
Luca
L
Fabris
Sonia
S
Baldini
Luca
L
Morabito
Fortunato
F
Bicciato
Silvio
S
Verdelli
Donata
D
Intini
Daniela
D
Nobili
Lucia
L
Cro
Lilla
L
Pruneri
Giancarlo
G
Callea
Vincenzo
V
Stelitano
Caterina
C
Maiolo
Anna Teresa
AT
Lombardi
Luigia
L
Neri
Antonino
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000032:analysis; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D007143:Immunoglobulin Heavy Chains; D007952:Leukemia, Plasma Cell / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000503:physiopathology*; D011379:Prognosis; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis; D014178:Translocation, Genetic; D015854:Up-Regulation
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D019947:Receptors, Interleukin-6