Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling
No citation available. Published: 2006.02.27
Jean-Pierre Bourquin, Aravind Subramanian, Claudia Langebrake, Dirk Reinhardt, Olivier Bernard, Paola Ballerini , Andri Baruchel, Hilhne Cavi, Nicole Dastugue, Henrik Hasle , Gertjan L Kaspers, Michel Lessard, Lucienne Michaux, Elisabeth van Wering, Christian M Zwaan, Todd R.Golub and Stuart H. Orkin
Read ManuscriptAbstract
Individuals with Down Syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by consistent somatic mutation of the transcription factor GATA1. As a result, DS-AMKL cells express an N-terminally truncated GATA1 protein, GATA1s. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison to genes regulated by GATA1 expression in murine erythroid precursors. Interestingly, genes that are repressed following GATA1 induction in the murine system, most notably GATA-2, MYC and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fails to repress this class of genes. In contrast, only a subset of genes that are upregulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Collectively, our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
Keywords: acute megakaryoblastic leukemia acute myeloid leukemia consensus clustering gene expression profiling leukemia
Supplemental Data
| Description | Link/Filename |
|---|---|
| AMKL dataset, raw CEL files | AMKL dataset.zip |
| GSEA results: crosspecies analysis with the G1-ER4 dataset | http://www.broad.mit.edu/personal/aravind/tmp/amkl/GSEA_data/Crossspecies/Crosspecies_GSEA_G1ERsystem/ |
| AMKL dataset, sample information file | Sample Information AMKL dataset.xls |
| GSEA results: St Jude gene sets on Boston dataset | http://www.broad.mit.edu/personal/aravind/tmp/amkl/GSEA_data/Crossvalidation/StJudesSets_BostonDataset/ |
| consensus clustering of non-DS AMKL | Consensus_Clustering_nonDS_AMKL.xls |
| GSEA results: Boston gene sets on St Jude dataset | http://www.broad.mit.edu/personal/aravind/tmp/amkl/GSEA_data/BostonSets_StJudeDataset/ |
| marker selection by SAM: DS-TMD vs. DS-AMKL | Marker_selection_SAM_DS_versus_TMD.xls |
| marker selection by SAM: DS-AMKL vs. non-DS-AMKL | Marker_selection_SAM_DS_vs_NDS.xls |
| predictor of DS-AMKL vs. non-DS-AMKL | PredictiionResults_d.xls |
| PDF copy of preprint | bourquin_pnas_2006.pdf |