The molecular classification of multiple myeloma.
To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.
Zhan
Fenghuang
F
Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Huang
Yongsheng
Y
Colla
Simona
S
Stewart
James P
JP
Hanamura
Ichiro
I
Gupta
Sushil
S
Epstein
Joshua
J
Yaccoby
Shmuel
S
Sawyer
Jeffrey
J
Burington
Bart
B
Anaissie
Elias
E
Hollmig
Klaus
K
Pineda-Roman
Mauricio
M
Tricot
Guido
G
van Rhee
Frits
F
Walker
Ronald
R
Zangari
Maurizio
M
Crowley
John
J
Barlogie
Bart
B
Shaughnessy
John D
JD
D002874:Chromosome Mapping; D016000:Cluster Analysis; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics; D003627:Data Interpretation, Statistical; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D009101:Multiple Myeloma / Q000145:classification* / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D010950:Plasma Cells / Q000276:immunology; D011379:Prognosis; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D053668:Syndecan-1; D053667:Syndecans
D056741:Cyclin D; D016213:Cyclins; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C508241:SDC1 protein, human; D053668:Syndecan-1; D053667:Syndecans