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Abstract
The differences in clinical course of chronic lymphocytic leukemia could have an impact on variations in a patient’s response to therapy. Our published results revealed that thermal transition (95 ± 5°C) in differential scanning calorimetry profiles appear to be characteristic for the advanced stage of CLL. Moreover, a decrease/loss of this transition in nuclei from leukemic cells exposed to drugs ex vivo could indicate their diverse efficacy. It seems that the lack of changes in thermal profile could predict patient’s drug resistance. In this study, we demonstrate the results obtained after drug treatment of leukemic cells by calorimetry, apoptosis-related parameters involved in expression of genes using cDNA microarray and western blot. These data were compared with the patients’ clinical parameters before and after RCC therapy (rituximab + cladribine + cyclophosphamide). The complementary analysis of studied cases with opposite clinical response (CR or NR) revealed a strong relationship between clinical data, differences in thermal scans and apoptosis-related gene expression. We quantified expression of eight of apoptosis-related 89 genes, i.e., NOXA, PUMA, APAF1, ESRRBL1, CASP3, BCL2, BCL2A1 and MCL1. Particular differences in NOXA and BCL2 expression were revealed. NOXA expression in cells of patients who achieved a complete response to RCC therapy was 0.44 times higher in comparison to control ones. Interestingly, in the case of patients who did not respond to immunotherapy, NOXA expression was highly downregulated (RQ = 4.39) as compared with untreated cells. These results were confirmed by distinct cell viability, protein expression as well as by differences in calorimetry profiles.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank Professor Paolo Ghia (Laboratory of B Cell Neoplasia, Division of Molecular Oncology, San Raffaele Scientific Institute) for sharing his expertise in VHJ mutational status assays. The study was partially supported by Grant No. PBZ/MNiSW/07/2006/28 from the Polish Ministry of Science and Higher Education, by Grant No. 2011/01/B/NZ4/01702 from Polish National Centre of Science, Poland; by statutory means No. 503/1–093–01/503–01 of the Hematology Department Medical University of Lodz, Poland; by the Foundation for Leukemia Sufferers, Poland and by the Foundation for the Development of Diagnostics and Therapy, Warsaw, Poland.