The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation

E. Rao, C. Jiang, M. Ji, X. Huang, Javeed Iqbal, G. Lenz, G. Wright, L. M. Staudt, Y. Zhao, T. W. McKeithan, W. C. Chan, Kai Fu

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.

Original languageEnglish (US)
Pages (from-to)1064-1072
Number of pages9
JournalLeukemia
Volume26
Issue number5
DOIs
StatePublished - May 2012

Fingerprint

Mantle-Cell Lymphoma
MicroRNAs
Phosphatidylinositol 3-Kinases
Growth
Neoplasms
Survival
Phosphoprotein Phosphatases
Gene Expression Profiling
Heterografts
Chromosomes
Apoptosis
Drug Therapy
Cell Line

Keywords

  • MiR-17B92 cluster
  • PHLPP2
  • PI3K/AKT pathway
  • PTEN
  • mantle cell lymphoma

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. / Rao, E.; Jiang, C.; Ji, M.; Huang, X.; Iqbal, Javeed; Lenz, G.; Wright, G.; Staudt, L. M.; Zhao, Y.; McKeithan, T. W.; Chan, W. C.; Fu, Kai.

In: Leukemia, Vol. 26, No. 5, 05.2012, p. 1064-1072.

Research output: Contribution to journalArticle

Rao, E, Jiang, C, Ji, M, Huang, X, Iqbal, J, Lenz, G, Wright, G, Staudt, LM, Zhao, Y, McKeithan, TW, Chan, WC & Fu, K 2012, 'The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation', Leukemia, vol. 26, no. 5, pp. 1064-1072. https://doi.org/10.1038/leu.2011.305
Rao, E. ; Jiang, C. ; Ji, M. ; Huang, X. ; Iqbal, Javeed ; Lenz, G. ; Wright, G. ; Staudt, L. M. ; Zhao, Y. ; McKeithan, T. W. ; Chan, W. C. ; Fu, Kai. / The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. In: Leukemia. 2012 ; Vol. 26, No. 5. pp. 1064-1072.
@article{1d6997dbf9564accab0d0fb462fefec3,
title = "The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation",
abstract = "The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.",
keywords = "MiR-17B92 cluster, PHLPP2, PI3K/AKT pathway, PTEN, mantle cell lymphoma",
author = "E. Rao and C. Jiang and M. Ji and X. Huang and Javeed Iqbal and G. Lenz and G. Wright and Staudt, {L. M.} and Y. Zhao and McKeithan, {T. W.} and Chan, {W. C.} and Kai Fu",
year = "2012",
month = "5",
doi = "10.1038/leu.2011.305",
language = "English (US)",
volume = "26",
pages = "1064--1072",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation

AU - Rao, E.

AU - Jiang, C.

AU - Ji, M.

AU - Huang, X.

AU - Iqbal, Javeed

AU - Lenz, G.

AU - Wright, G.

AU - Staudt, L. M.

AU - Zhao, Y.

AU - McKeithan, T. W.

AU - Chan, W. C.

AU - Fu, Kai

PY - 2012/5

Y1 - 2012/5

N2 - The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.

AB - The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.

KW - MiR-17B92 cluster

KW - PHLPP2

KW - PI3K/AKT pathway

KW - PTEN

KW - mantle cell lymphoma

UR - http://www.scopus.com/inward/record.url?scp=84860755726&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860755726&partnerID=8YFLogxK

U2 - 10.1038/leu.2011.305

DO - 10.1038/leu.2011.305

M3 - Article

C2 - 22116552

AN - SCOPUS:84860755726

VL - 26

SP - 1064

EP - 1072

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 5

ER -