Epigenetic regulation of cathepsin L expression in chronic myeloid leukemia

Samaiya, Misti ; Bakhshi, Sameer ; Shukla, Abhay A. ; Kumar, Lalit ; Chauhan, Shyam S. (2011) Epigenetic regulation of cathepsin L expression in chronic myeloid leukemia Journal of Cellular and Molecular Medicine, 15 (10). pp. 2189-2199. ISSN 1582-1838

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Official URL: http://onlinelibrary.wiley.com/doi/10.1111/j.1582-...

Related URL: http://dx.doi.org/10.1111/j.1582-4934.2010.01203.x

Abstract

The expression and significance of cathepsin L (CTSL) has been extensively studied in solid tumours. However no such information in chronic myeloid leukaemia (CML) was available. We investigated the activity and expression of this protease in peripheral blood mononuclear cells (PBMCs) of 47 adult CML patients. Thirty adults suffering from systemic diseases and 50 healthy volunteers served as controls. The mRNA levels of CTSL, its specific endogenous inhibitor cystatin C and transcriptional up-regulator vascular endothelial growth factor (VEGF) were quantitated by real-time qPCR. CTSL protease activity and its mRNA expression were significantly higher in CML chronic phase (CP) patients compared to CML accelerated phase/blast crisis (AP/BC) patients and controls (P ≤ 0.001). VEGF whose expression was most pronounced in CP and declined (P ≤ 0.001) in the advanced phases of the malignancy exhibited a strong positive correlation with CTSL expression (r= 0.97; P ≤ 0.001). Cystatin C expression was significantly lower (P ≤ 0.001) in CML and displayed inverse correlation with CTSL (r=−0.713; P ≤ 0.001) activity. CTSL promoter was significantly hypomethylated in CML CP compared to CML AP/BC patients as well as controls. K562, a BC CML cell line displayed CTSL activity, expression and methylation status of CTSL promoter that was comparable to CML AP/BC patients. Treatment of these cells or PBMCs isolated from CML AP/BC patients with 5'-aza-cytidine resulted in a dramatic increase in CSTL activity and/or expression thereby demonstrating the role of promoter methylation in the stage specific expression of CTSL in CML. Differential expression of CTSL in CML at various stages of malignancy may prove useful in identification of the high-risk patients thereby facilitating better management of disease.

Item Type:Article
Source:Copyright of this article belongs to Carol Davila University of Medicine Bucharest, Romania.
Keywords:Cathepsin L (CTSL); Chronic Myeloid Leukemia (CML); Vascular Endothelial Growth Factor (VEGF); Promoter Methylation; k562
ID Code:66827
Deposited On:27 Oct 2011 06:44
Last Modified:27 Oct 2011 06:44

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