Oncotarget

Research Papers:

Different BCR/Abl protein suppression patterns as a converging trait of chronic myeloid leukemia cell adaptation to energy restriction

Silvia Bono, Matteo Lulli, Vito Giuseppe D’Agostino, Federico Di Gesualdo, Rosa Loffredo, Maria Grazia Cipolleschi, Alessandro Provenzani, Elisabetta Rovida and Persio Dello Sbarba _

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Oncotarget. 2016; 7:84810-84825. https://doi.org/10.18632/oncotarget.13319

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Abstract

Silvia Bono1, Matteo Lulli1, Vito Giuseppe D’Agostino2, Federico Di Gesualdo1, Rosa Loffredo2, Maria Grazia Cipolleschi1, Alessandro Provenzani2, Elisabetta Rovida1, Persio Dello Sbarba1

1Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Università degli Studi di Firenze, Florence, Italy

2Centre For Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy

Correspondence to:

Persio Dello Sbarba, email: persio@unifi.it

Matteo Lulli, email: matteo.lulli@unifi.it

Elisabetta Rovida, email: elisabetta.rovida@unifi.it

Keywords: transcriptional regulation, translational regulation, post-translational regulation, hypoxia, glucose shortage

Received: August 11, 2016     Accepted: October 28, 2016     Published: November 12, 2016

ABSTRACT

BCR/Abl protein drives the onset and progression of Chronic Myeloid Leukemia (CML). We previously showed that BCR/Abl protein is suppressed in low oxygen, where viable cells retain stem cell potential. This study addressed the regulation of BCR/Abl protein expression under oxygen or glucose shortage, characteristic of the in vivo environment where cells resistant to tyrosine kinase inhibitors (TKi) persist. We investigated, at transcriptional, translational and post-translational level, the mechanisms involved in BCR/Abl suppression in K562 and KCL22 CML cells. BCR/abl mRNA steady-state analysis and ChIP-qPCR on BCR promoter revealed that BCR/abl transcriptional activity is reduced in K562 cells under oxygen shortage. The SUnSET assay showed an overall reduction of protein synthesis under oxygen/glucose shortage in both cell lines. However, only low oxygen decreased polysome-associated BCR/abl mRNA significantly in KCL22 cells, suggesting a decreased BCR/Abl translation. The proteasome inhibitor MG132 or the pan-caspase inhibitor z-VAD-fmk extended BCR/Abl expression under oxygen/glucose shortage in K562 cells. Glucose shortage induced autophagy-dependent BCR/Abl protein degradation in KCL22 cells. Overall, our results showed that energy restriction induces different cell-specific BCR/Abl protein suppression patterns, which represent a converging route to TKi-resistance of CML cells. Thus, the interference with BCR/Abl expression in environment-adapted CML cells may become a useful implement to current therapy.


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