The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma.
We used gene expression profiling to establish a molecular diagnosis of mantle cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of survival of these patients. An MCL gene expression signature defined a large subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1 expression. A precise measurement of tumor cell proliferation, provided by the expression of proliferation signature genes, identified patient subsets that differed by more than 5 years in median survival. Differences in cyclin D1 mRNA abundance synergized with INK4a/ARF locus deletions to dictate tumor proliferation rate and survival. We propose a quantitative model of the aberrant cell cycle regulation in MCL that provides a rationale for the design of cell cycle inhibitor therapy in this malignancy.
Rosenwald
Andreas
A
The Lymphoma/Leukemia Molecular Profiling Project, National Cancer Institute/NIH, Bethesda, MD, USA.
Wright
George
G
Wiestner
Adrian
A
Chan
Wing C
WC
Connors
Joseph M
JM
Campo
Elias
E
Gascoyne
Randy D
RD
Grogan
Thomas M
TM
Muller-Hermelink
H Konrad
HK
Smeland
Erlend B
EB
Chiorazzi
Michael
M
Giltnane
Jena M
JM
Hurt
Elaine M
EM
Zhao
Hong
H
Averett
Lauren
L
Henrickson
Sarah
S
Yang
Liming
L
Powell
John
J
Wilson
Wyndham H
WH
Jaffe
Elaine S
ES
Simon
Richard
R
Klausner
Richard D
RD
Montserrat
Emilio
E
Bosch
Francesc
F
Greiner
Timothy C
TC
Weisenburger
Dennis D
DD
Sanger
Warren G
WG
Dave
Bhavana J
BJ
Lynch
James C
JC
Vose
Julie
J
Armitage
James O
JO
Fisher
Richard I
RI
Miller
Thomas P
TP
LeBlanc
Michael
M
Ott
German
G
Kvaloy
Stein
S
Holte
Harald
H
Delabie
Jan
J
Staudt
Louis M
LM
D020727:ADP-Ribosylation Factors / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D019938:Cyclin D1 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D020506:Untranslated Regions / Q000235:genetics
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D020506:Untranslated Regions; D019938:Cyclin D1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D020727:ADP-Ribosylation Factors