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

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Abstract

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

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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