Acute myeloid leukemia : apoptotic signalling and gene expression associated with treatment response

摘要: Acute myeloid leukemia (AML) is a severe, life threatening malignancy characterized by clonal expansion of immature cells in the bone marrow, resulting severe infections and bleedings. High dose chemotherapy able to normalize blood marrow morphology (complete remission, CR) majority treated patients, but recurrent disease, typically occurs within 1-2 years. Since further intensification chemotherapeutic regimens usually ineffective accompanied excess toxicity, novel approaches using better-targeted drugs are now being assessed. We have analysed effects one such new agent, gemtuzumab ozogamicin (GO) on AML also looked for biomarkers clinical response role multidrug resistance (MDR) expression utilizing biobanked from an cohort with known long-term therapuetic outcome. In paper I we apoptotic signalling GO, monoclonal CD33 antibody conjugated DNA-double strand break-inducing toxin calicheamicin. The antigen expressed blast cells, not e.g. normal gut cells. found that GO could induce mitochondrial depolarisation, activation caspase-3 decreased viability primary patients cell lines. Moreover, showed activated proapoptotic proteins Bak Bax, regulators mitochondria-mediated signalling. Importantly, none above events be observed GO-resistant II, at caspase-2 GOor daunorubicin-induced noted both caused cleavage into its active form. A selective inhibitor prevented GO-induced activation, yet did influence Bax. All all, our data indicate mitochondria-dependent independent routes involved signalling, findings may lead future therapeutic AML. Improved predictive treatment clearly needed enable more personalized effective options III studied peripheral 42 diagnosed subjected induction chemotherapy, aiming identify CR duration global gene analysis (Affymetrix). Prominent differences were remarkable up-regulation transcription factor RUNX1T1 short vs. those long subsequent duration. Network analyses (Oncomine) revealed multiple factors as interactors RUNX1T1, out which TCF3 was significantly up-regulated An silico validation, taking advantage previously published two other cohorts 52 genes regulated all three cohorts. Among these CXCL3, ZMIZ1 PRDX2 attracted special interest due their reported involvement cancer, leukemia, apoptosis proliferation. Thus, CXCL3 ZMIZ1, tumorgenesis, had increased poor responders whereas PRDX2, tumour suppressor gene, instead expression. IV investigated relevance 380 genes, analyzed 11 paired sampled collected diagnosis time relapse. Unsupervised hierarchical clustering half cases similar pattern points, remaining MDR became altered, suggesting evolution. Patient-by-patient signs unique individual patient signatures 10 increase least ABC transporter These call broad diagnostic relapse blasts order improve thereby overall survival patient. LIST OF PUBLICATIONS I. Petra Haag, Kristina Viktorsson, Marita Lagergren Lindberg, Lena Kanter, Rolf Lewensohn, Leif Stenke. Deficient Bax confers ozogamicin-induced death Experimental Hematology, 2009, June;37(6):755-66 II. Dali Zong, Magnus Olsson, Boris Zhivotovsky, Bo Stenerlow, Stenke Viktorsson. Caspase-2 plays mitochondria-independent signaling daunorubicin acute leukemia. Manuscript, 2013 III. Ali Moshfegh, Bjorkholm, Viktorsson Gene IV. Chirayu Patel, Stenke, Sudhir Varma, Jan Sjoberg, Ola Landgren, Michael M Gottesman, Jean-Pierre Gillet. Multidrug Resistance Relapsed Myeloid Leukemia: Evidence Biological Heterogeneity. Cancer. May 14. doi: 10.1002/cncr.28098.