Molecular mechanisms of alpha-particle-induced cytotoxicity in human leukemic cells as revealed by gene-expression profiling


Simona Martin1, Ralf Kronenwett2, Katia Vandenbulcke3, Fritz Offner4, Slawomir Kliszewski2, Christos Apostolidis1, Ramon Carlos1, Willem Janssens1, Maurice Leroy1, Tuomo Nikula1, Jan Philippe4, and Rainer Haas2. (1) Nuclear Chemistry, European Commission, Joint Research Centre, Institute for Transuranium Elements, PO Box 2340, Karlsruhe, 76125, Germany, (2) Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Duesseldorf, Germany, (3) Department of Radiopharmacy, University of Gent, Gent, Belgium, (4) Department of Hematology, University of Gent, Gent, Belgium
Alpha-particle emitters such as 213Bi with high LET and short path length kill cells by few nuclear hits. Little is known about the molecular pathways of alpha-induced cytotoxicity in human cancer cells. Our study was aimed to identify the transcriptional responses induced in peripheral blood lymphocytes from 12 patients with B-chronic lymphocytic leukemia (CLL) after in vitro treatment with 213Bi-CHX-A-DTPA-anti-CD20. Using cDNA arrays comprising 1,185 genes we intraindividually compared expression profiles of treated and non-treated cells and identified 66 genes significantly altered after treatment. These include genes coding for DNA-replication proteins, basic transcription factors, cell cycle regulators, adhesion and death receptors, growth factors, chemokines. As B-CLL cells differ according to the immunoglobulin (Ig) mutational status, we found significantly different responses between cells from patients with mutated and unmutated rearranged Ig genes. Our results give insights into the molecular effects of alpha-irradiation and provide information on cell-type-specific molecular responses.