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Proc Natl Acad Sci U S A DOI:10.1073/pnas.0511150103

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

Publication TypeJournal Article
Year of Publication2006
AuthorsBourquin, J-P, Subramanian, A, Langebrake, C, Reinhardt, D, Bernard, O, Ballerini, P, Baruchel, A, Cavé, H, Dastugue, N, Hasle, H, Kaspers, GL, Lessard, M, Michaux, L, Vyas, P, van Wering, E, Zwaan, CM, Golub, TR, Orkin, SH
JournalProc Natl Acad Sci U S A
Date Published2006 Feb 28
KeywordsChromosomes, Human, Pair 21, Core Binding Factor Alpha 2 Subunit, Down Syndrome, GATA1 Transcription Factor, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Megakaryoblastic, Acute, Multigene Family, Phenotype, Transcription Factors

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID16492768
PubMed Central IDPMC1413912