Gene Expression Profiling Identifies a Prognostically Favorable Subgroup in AML Independent of Cytogenetic Stratification.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases with varying clinical outcome. So far the karyotype of the leukemic blasts as well as molecular genetic abnormalities - both abnormalities on the genomic level - have been proven to be strong prognostic markers. However, even in genetically well defined subgroups clinical outcome is not uniform and a large proportion of AML shows genetic abnormalities of yet unknown prognostic significance. Here we addressed the question whether gene expression profiles are associated with clinical outcome independent of the known genomic abnormalities. Therefore, gene expression analyses were performed using Affymetrix U133A+B oligonucleotide microarrays in a total of 403 AML treated uniformly in the AMLCG studies. This cohort was divided randomly into a training set (n=269) and a test set (n=134). The training set included 18 cases with t(15;17), 22 cases with t(8;21), 29 cases with inv(16), 14 cases with 11q23/MLL-rearrangement, 19 with complex aberrant karyotype and 167 cases with normal karyotype or “other” chromosome aberrations. The respective data for the test set were: 10 t(15;17), 8 t(8;21), 11 inv(16), 8 11q23/MLL, 19 cases with complex aberrant karyotype and 78 with normal karyotype or “other” chromosome aberrations. Based on the clinical outcome the training cohort was divided into 4 equally large subgroups. We trained support vector machines (SVM) with the training set and classified the cases of the test set with the respective most discriminating genes. Next a Kaplan-Meier analysis was performed with the test set cases assigned to prognostic groups 1 to 4 according to SVM classification. Based on the expression level of 100 genes group 1 showed an overall survival rate of 57% at 3 years. 31 of 134 (23%) patients were assigned to this favorable subgroup. They belonged to the following cytogenetic subgroups: t(15;17) n=6, t(8;21) n=4, inv(16) n=3, 11q23/MLL n=4, complex aberrant karyotype n=1 and normal karyotype or “other” chromosome aberration n=13. The overall survival rate of groups 2, 3, and 4 did not differ significantly (17%, 21%, and 19% at 3 years). Among the genes highly expressed in the favorable group were MPO and the transcription factor ATBF1, which regulates CCND1. The unfavorable groups were characterized by a higher expression of the transcription factors ETS2, RUNX1, TCF4, and FOXC1. Interestingly, 10 of the top 40 differentially expressed genes are involved in the TP53-CMYC-pathway with a higher expression of 9 of these in the unfavorable groups (SFRS1, TPD52, NRIP1, TFPI, UBL1, REC8L1, HSF2, ETS2 and RUNX1). In conclusion, gene expression profiling leads to the identification of prognostically important alterations of molecular pathways which have not yet been accounted for by use of cytogenetics. This approach is anticipated to help optimizing therapy for patients with AML.