Obiettivo The objective of my project is to analyse the MLL gene (11q23) and other loci rearrangements induced by topoisomerase II (topoII) inhibitors in hematopoietic stem cells. It is known that prior exposure to topo II inhibitors (e.g. etoposide) can result in subsequent development of therapy-related leukemias with MLL translocations, which are fatal complications of effective cancer treatment. Also, in utero exposure to environmental topoII inhibitors can lead to MLL infants' leukemias. Etoposide causes DNA damage in form of double strand breaks in DNA (DSBs), activation of p53 and induce cell death. DSBs in DNA are at a high risk for producing chromosomal rearrangements if cells aberrantly repair DNA. However, the mechanisms by which the specific aberration occurs are unclear.To address these issues, I developed an in vitro hematopoietic CD34+ stem cell culture model of etoposide exposure and recovery (Libura et al, 2005) and analysed MLL rearrangements by inverse PCR (IPCR) and fluorescence in situ hybridisation (FISH). My results clearly demonstrated that sublethal exposure of CD34+ cells to etoposide results in numerous aberrations in MLL gene fragment flanking topo II cleavage hot spots. In this study I will extend the previous analysis on the entire 8.2kb MLL bcr locus as well as other loci, with particular focus on primitive stem cells. In addition, I will analyse the biological significance of in vitro aberrations and determine if my experimental results are analogous to in vivo exposure by examination of blood from cancer patients during chemotherapy.The results of my study might provide new ways for prevention of fatal MLL leukemia. Project matches perfectly the main priorities of 6 Framework Program by promoting transactional mobility for training purpose s, the development of expertise and transfer of knowledge in DNA repair mechanisms and MLL research. Mobility will help to develop world-class human recourses and research excellence in Poland and EU. Campo scientifico natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncologyleukemia Parole chiave MLL BCR infants' leukemia therapy-related leukemia topoisomerase II inhibitors Programma(i) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Argomento(i) MOBILITY-2.2 - Marie Curie Outgoing International Fellowships (OIF) Invito a presentare proposte FP6-2002-MOBILITY-6 Vedi altri progetti per questo bando Meccanismo di finanziamento OIF - Marie Curie actions-Outgoing International Fellowships Coordinatore AKADEMIA MEDYCZNA W WARSZAWIE/MEDICAL UNIVERSITY OF WARSAW Contributo UE Nessun dato Indirizzo Zwirki i Wigury 61 WARSZAWA Polonia Mostra sulla mappa Collegamenti Sito web Opens in new window Costo totale Nessun dato Partecipanti (1) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto COLUMBIA UNIVERSITY Stati Uniti Contributo UE Nessun dato Indirizzo 1150 St Nicholas Av., RBP, room 318 NEW YORK Mostra sulla mappa Collegamenti Sito web Opens in new window Costo totale Nessun dato
