miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator.
Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2 trial (screening cohort). Prognostic miRNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression-free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.
Department of Hematology and.
Simon
S
Husby
Department of Hematology and Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;
Ulrik
U
Ralfkiaer
Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark; Center for non-coding RNA in Technology and Health, Department of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
Christian
C
Garde
Department of Hematology and.
Roza
R
Zandi
Department of Immunotechnology, CREATE Health, Lund University, Lund, Sweden;
Sara
S
Ek
Departments of Oncology and Pathology, Rikshospitalet, Oslo, Norway;
Arne
A
Kolstad
Department of Oncology, Skåne University Hospital, Lund, Sweden;
Mats
M
Jerkeman
Department of Oncology, Uppsala University Hospital, Uppsala, Sweden;
Anna
A
Laurell
Departments of Hematology and Oncology, Helsinki University Central Hospital, Helsinki, Finland;
Riikka
R
Räty
Department of Hematology and.
Lone B
LB
Pedersen
Department of Hematology and.
Anja
A
Pedersen
Department of Pathology, Skåne University Hospital, Lund, Sweden;
Mats
M
Ehinger
Department of Immunology, Genetics, and Pathology, Uppsala University Hospital, Uppsala, Sweden;
Christer
C
Sundström
Department of Pathology, Laboratory Diagnostics, Helsinki University Central Hospital, Helsinki, Finland; and.
Marja-Liisa
ML
Karjalainen-Lindsberg
Department of Pathology, Division of Cancer Medicine and Surgery, Oslo University Hospital, Oslo, Norway.
Jan
J
Delabie
Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;
Erik
E
Clasen-Linde
Department of Hematology and.
Peter
P
Brown
Department of Hematology and.
Jack B
JB
Cowland
Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark; Center for non-coding RNA in Technology and Health, Department of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
Christopher T
CT
Workman
Department of Hematology and.
Christian H
CH
Geisler
Department of Hematology and.
Kirsten
K
Grønbæk
D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D014162:Transfection; D015854:Up-Regulation
D014408:Biomarkers, Tumor; C540193:MIrn181 microRNA, human; D035683:MicroRNAs