E-SMDB-3491 - Transcription profiling of adult acute myeloid leukemia associated with drug resistance
Released on 30 November 2005, last updated on 27 March 2012
Acute myeloid leukemia (AML) patients are primarily resistant to induction chemotherapy in 20-50%. Previously it has been shown that resistance to the first cycle of induction chemotherapy is an independent prognostic factor. We investigated whether resistance to chemotherapy can be represented by gene-expression profiling, and which genes are associated with resistance. cDNA microarrays containing ~41.000 features were used to compare the gene-expression profile of AML blasts between 33 patients with good or poor response to induction chemotherapy. Data generated by cDNA-arrays were confirmed by quantitative RT-PCR. Using Significance Analysis of Microarrays, we identified a characteristic gene-expression profile which distinguished good- from poor-response AML samples. In hierarchical clustering analysis poor responders clustered together with normal CD34+ cells. Moreover, 13/40 (32.5%) genes highly expressed in poor responders are also overexpressed in hematopoietic stem/progenitor cells. Prediction analysis using 10-fold crossvalidation revealed 80% overall accuracy. Using the treatment response signature to predict the outcome in an independent test set of 104 AML patients, samples were separated into two subgroups with significantly inferior response rate (43.5% vs. 66.7%, P=.044), significantly shorter event-free and overall survival (P=.01 and P=.03, respectively) in the poor-response compared to the good-response signature group. In multivariate analysis, the treatment-response signature was an independent prognostic factor (hazard ratio, 2.1, 95 percent-confidence interval 1.2 to 3.6, P=.006). Resistance to chemotherapy in AML can be identified by gene-expression profiling before treatment and seems to be mediated by a transcriptional program active in hematopoietic stem/progenitor cells.
transcription profiling by array, all pairs
Gene-expression profiles and their association with drug resistance in adult acute myeloid leukemia. Heuser M, Wingen LU, Steinemann D, Cario G, von Neuhoff N, Tauscher M, Bullinger L, Krauter J, Heil G, Dohner H, Schlegelberger B, Ganser A.