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miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator.

Husby, Simon; Ralfkiaer, Ulrik; Garde, Christian; Zandi, Roza; Ek, Sara; Kolstad, Arne; Jerkeman, Mats LU ; Laurell, Anna LU ; Räty, Riikka and Pedersen, Lone Bredo, et al. (2015) In Blood 125(17). p.2669-2677
Abstract
Recent studies show that mantle cell lymphoma (MCL) express aberrant miRNA profiles, however, the clinical effect of miRNA expression has not previously been examined and validated in prospective, large, homogenously treated cohorts. We analyzed diagnostic MCL samples from the Nordic MCL2 and MCL3 clinical trials, in which all patients had received Rituximab-high-dose cytarabin alternating with Rituximab-maxiCHOP, followed by BEAM and autologous stem cell support. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the MCL2 trial (screening cohort). Differentially expressed miRNAs were re-analyzed by qRT-PCR. Prognostic miRNAs were validated by qRT-PCR in diagnostic MCL samples from 94 patients of the... (More)
Recent studies show that mantle cell lymphoma (MCL) express aberrant miRNA profiles, however, the clinical effect of miRNA expression has not previously been examined and validated in prospective, large, homogenously treated cohorts. We analyzed diagnostic MCL samples from the Nordic MCL2 and MCL3 clinical trials, in which all patients had received Rituximab-high-dose cytarabin alternating with Rituximab-maxiCHOP, followed by BEAM and autologous stem cell support. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the MCL2 trial (screening cohort). Differentially expressed miRNAs were re-analyzed by qRT-PCR. Prognostic miRNAs were validated by qRT-PCR in diagnostic MCL samples from 94 patients of the independent MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, miR-378d) were significantly differentially expressed in patients who died from MCL in both the screening- and the validation cohort. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new MIPI-B-miR prognosticator, combining expression-levels of miR-18b with MIPI-B data. This prognosticator improved identification of high risk patients compared to MIPI-B with regard to cause-specific survival (P=0.015), overall survival (P=0.006) and progression-free survival (P<0.001). Transfection of two MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. Thus, we conclude that overexpression of miR-18b identifies patients with poor prognosis in two large prospective MCL cohorts and adds prognostic information to MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance. (Less)
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Contribution to journal
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published
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Blood
volume
125
issue
17
pages
2669 - 2677
publisher
American Society of Hematology
external identifiers
  • pmid:25736311
  • wos:000355653600015
  • scopus:84928910823
ISSN
1528-0020
DOI
10.1182/blood-2014-06-584193
language
English
LU publication?
yes
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b0e7b39d-f3e4-416e-879f-da99cc381557 (old id 5265366)
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http://www.ncbi.nlm.nih.gov/pubmed/25736311?dopt=Abstract
date added to LUP
2015-04-01 18:10:38
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2017-11-12 03:09:26
@article{b0e7b39d-f3e4-416e-879f-da99cc381557,
  abstract     = {Recent studies show that mantle cell lymphoma (MCL) express aberrant miRNA profiles, however, the clinical effect of miRNA expression has not previously been examined and validated in prospective, large, homogenously treated cohorts. We analyzed diagnostic MCL samples from the Nordic MCL2 and MCL3 clinical trials, in which all patients had received Rituximab-high-dose cytarabin alternating with Rituximab-maxiCHOP, followed by BEAM and autologous stem cell support. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the MCL2 trial (screening cohort). Differentially expressed miRNAs were re-analyzed by qRT-PCR. Prognostic miRNAs were validated by qRT-PCR in diagnostic MCL samples from 94 patients of the independent MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, miR-378d) were significantly differentially expressed in patients who died from MCL in both the screening- and the validation cohort. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new MIPI-B-miR prognosticator, combining expression-levels of miR-18b with MIPI-B data. This prognosticator improved identification of high risk patients compared to MIPI-B with regard to cause-specific survival (P=0.015), overall survival (P=0.006) and progression-free survival (P&lt;0.001). Transfection of two MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. Thus, we conclude that overexpression of miR-18b identifies patients with poor prognosis in two large prospective MCL cohorts and adds prognostic information to MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.},
  author       = {Husby, Simon and Ralfkiaer, Ulrik and Garde, Christian and Zandi, Roza and Ek, Sara and Kolstad, Arne and Jerkeman, Mats and Laurell, Anna and Räty, Riikka and Pedersen, Lone Bredo and Pedersen, Anja and Ehinger, Mats and Sundström, Christer and Karjalainen-Lindsberg, Marja-Liisa and Delabie, Jan and Clasen-Linde, Erik and Brown, Peter and Cowland, Jack and Workman, Christopher T and Geisler, Christian H and Grønbæk, Kirsten},
  issn         = {1528-0020},
  language     = {eng},
  number       = {17},
  pages        = {2669--2677},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator.},
  url          = {http://dx.doi.org/10.1182/blood-2014-06-584193},
  volume       = {125},
  year         = {2015},
}