STANDARD_NAME MUELLER_COMMON_TARGETS_OF_AML_FUSIONS_UP SYSTEMATIC_NAME M2289 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/MUELLER_COMMON_TARGETS_OF_AML_FUSIONS_UP NAMESPACE AFFY_HuGene DESCRIPTION_BRIEF Up-regulated target genes shared by acute myeloid leukemia (AML) translocation products PML RARA [GeneID=5371;5914], AML1 ETO [GeneID=861;862], and PLZF RARA [GeneID=5914;7704]. DESCRIPTION_FULL The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. beta-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML. PMID 15024077 GEOID AUTHORS Müller-Tidow C,Steffen B,Cauvet T,Tickenbrock L,Ji P,Diederichs S,Sargin B,Köhler G,Stelljes M,Puccetti E,Ruthardt M,deVos S,Hiebert SW,Koeffler HP,Berdel WE,Serve H CONTRIBUTOR Arthur Liberzon CONTRIBUTOR_ORG MSigDB Team EXACT_SOURCE Table 1: Induced FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS D16480_at,D31764_at,D63391_at,D83782_at,L36983_at,L76702_at,M16279_at,M31523_at,M57567_at,U65093_at,X70683_at,X73358_s_at,Z36714_at,Z68228_s_at GENE_SYMBOLS HADHA,SNX17,PAFAH1B3,SCAP,DNM2,PPP2R5D,CD99,TCF3,ARF5,CITED2,SOX4,TLE5,CCNF,JUP FOUNDER_NAMES