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Haematologica. 2010 May;95(5):760-7. doi: 10.3324/haematol.2009.014050. Epub 2009 Dec 16.

C/EBPβ expression in ALK-positive anaplastic large cell lymphomas is required for cell proliferation and is induced by the STAT3 signaling pathway.

Author information

1
Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Germany.

Abstract

BACKGROUND:

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma is characterized by the t(2;5) chromosomal translocation, resulting in the expression of a fusion protein formed of nucleophosmin (NPM) and ALK. Recently, we reported the abnormal expression of the transcription factor CCAAT/enhancer binding protein-beta (C/EBPbeta) in ALK-positive anaplastic large cell lymphomas, and demonstrated its dependence on NPM-ALK activity.

DESIGN AND METHODS:

In this study, the role of C/EBPbeta in proliferation and survival of ALK-positive anaplastic large cell lymphomas was investigated, as well as the mechanism of its expression and activity. Highly effective short hairpin RNA sequences and/or pharmacological inhibitors were used to abrogate the expression or activity of C/EBPbeta, signal transducer and activator of transcription 3 (STAT3), AKT, extracellular signal-related kinase 1/2 (ERK1/2) and mammalian target of rapamycin (mTOR).

RESULTS:

Interference with C/EBPbeta expression resulted in a dramatic decrease in cell proliferation in ALK-positive anaplastic large cell lymphomas, with a mild induction of apoptosis after 6 days. Down-regulation of STAT3 resulted in a marked decrease in C/EBPbeta mRNA and protein levels with impairment in cell proliferation and viability, underscoring the important role of these two proteins in ALK-mediated oncogenesis. Additionally, we demonstrated that reduction of ERK1/2 activity led to C/EBPbeta Thr(235) dephosphorylation and moderate growth retardation. The AKT/mTOR signaling pathway did not have any influence on C/EBPbeta expression or C/EBPbeta phosphorylation.

CONCLUSIONS:

These findings reveal the convergence of STAT3 and ERK1/2 signaling pathways activated by NPM-ALK in mediating the regulation of C/EBPbeta expression, a transcription factor central to NPM-ALK transformation.

PMID:
20015877
PMCID:
PMC2864382
DOI:
10.3324/haematol.2009.014050
[Indexed for MEDLINE]
Free PMC Article

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