Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling

Jean Pierre Bourquin, Aravind Subramanian, Claudia Langebrake, Dirk Reinhardt, Olivier Bernard, Paola Ballerini, André Baruchel, Hélène Cavé, Nicole Dastugue, Henrik Hasle, Gertjan L. Kaspers, Michel Lessard, Lucienne Michaux, Paresh Vyas, Elisabeth Van Wering, Christian M. Zwaan, Todd R. Golub, Stuart H. Orkin

Research output: Contribution to journalArticlepeer-review

161 Citations (Scopus)

Abstract

Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. 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 with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated 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. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.

Original languageEnglish
Pages (from-to)3339-3344
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number9
DOIs
Publication statusPublished - 28 Feb 2006
Externally publishedYes

Keywords

  • Down syndrome
  • GATA1

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