Sensitivity of leukemic T-cell lines to arsenic trioxide cytotoxicity is dependent on the induction of phosphatase B220/CD45R expression at the cell surface

Molecular Cancer

Research

Amine Mellouk¹  Mohcine Benbijja²  Pierre Bobé³ 

[1] INSERM U757, Université Paris-Sud, Orsay, France;Institut Jacques Monod, CNRS, Université Paris Diderot, Paris, France;INSERM U1012, Université Paris-Sud, Le Kremlin Bicêtre, Orsay, France;Institut Jacques Monod, CNRS, Université Paris Diderot, Paris, France;INSERM U757, Université Paris-Sud, Orsay, France;

关键词: AsO-based therapy;    Leukemia;    T lymphocyte;    Membrane tyrosine-phosphatase B220/CD45R;    Membrane-bound HSP70;    Fas/Fas ligand pathway;    Cell death;    Caspase activation;    NF-κB p50;   

DOI  :  10.1186/1476-4598-13-251

 received in 2014-01-16, accepted in 2014-11-06,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundArsenic trioxide (As2O3) is highly effective in treating acute promyelocytic leukemia (APL), but shows more variable therapeutic efficacy for other types of hematological malignancies. Previously, we reported that As2O3 selectively eliminates pathogenic B220-expressing T cells in autoimmune MRL/lpr mice. We investigated herein the relationship between As2O3 sensitivity of leukemic T-cell lines and the expression levels of the B220 isoform of transmembrane tyrosine phosphatase CD45.MethodsGSH content, O2- production, and B220, HSP70, Fas and FasL membrane expression was measured by flow cytometry. Subcellular localization of B220 was determined by imaging flow cytometry. Cell death was analyzed by morphological changes, annexin V and propidium iodide staining, and caspase 8 and 9 activation. B220 mRNA expression was analyzed by RT-PCR. Activated NF-κB p50 was quantified by a DNA binding ELISA.ResultsWe selected human (Jurkat, Jurkat variant J45.01, HPB-ALL) and mouse (EL-4, BW5147, L1210) T-cell lines for their marked differences in As2O3 sensitivity over a large range of doses (1 to 20 μM). Differences in redox status cannot explain the dramatic differences in As2O3 sensitivity observed among the T-cell lines. Unexpectedly, we found that B220 is differentially induced on As2O3-treated T-cell lines. As2O3 treatment for 24 h induced low (HPB-ALL), intermediate (Jurkat) and high (EL-4, BW5147) levels of B220 membrane expression, membrane-bound HSP70 and cell death, but inhibited NF-κB p50 nuclear translocation. When high levels of B220 expression were achieved with low doses of As2O3, the T-cell lines died by apoptosis only. When high doses of As2O3 were required to induce B220 expression, leukemic T cells died by both apoptosis and necrosis.ConclusionsCellular redox status is not essential for As2O3 sensitivity of leukemic T cells, suggesting the existence of additional factors determining their sensitivity to As2O3 cytotoxicity. Phosphatase B220 could be such a factor of sensitivity. As2O3 treatment inhibits NF-κB p50 nuclear translocation, and induces B220 expression and cell death in a dose and time dependent manner. The levels of B220 induction on leukemic T cells strictly correlate with both the extent and form of cell death, B220 might therefore play a checkpoint role in death pathways.

【 授权许可】

Unknown   
© Benbijja et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.