title: Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein.
abstract: E2A-PBX1 is expressed as a result of the t(1;19) chromosomal translocation in nearly 5% of cases of childhood acute lymphoblastic leukemia. The E2A-PBX1 chimeric transcription factor contains the N-terminal transactivation domain of E2A (TCF3) fused to the C-terminal DNA-binding homeodomain of PBX1. While there is no doubt of its oncogenic potential, the mechanisms of E2A-PBX1-mediated pre-B cell transformation and the nature of direct E2A-PBX1 target genes and pathways remain largely unknown. Herein we used chromatin immunoprecipitation assays (ChIP-chip) to identify direct targets of E2A-PBX1, and we used gene expression arrays of siRNA E2A-PBX1-silenced cells to evaluate changes in expression induced by the fusion protein. Combined ChIP-chip and expression data analysis gave rise to direct and functional targets of E2A-PBX1. Further we observe that the set of ChIP-chip identified E2A-PBX1 targets show a collective down-regulation trend in the E2A-PBX1 silenced samples compared to controls suggesting an activating role of this fusion transcription factor. Our data suggest that the expression of the E2A-PBX1 fusion gene interferes with key regulatory pathways and functions of hematopoietic biology. Among these are members of the WNT and apoptosis/cell cycle control pathways, and thus may comprise an essential driving force for the propagation and maintenance of the leukemic phenotype. These findings may also provide evidence of potentially attractive therapeutic targets.
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America ; Department of Pediatrics, St Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.
authors: Christofer
authors: C
authors: Diakos
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors: Yuanyuan
authors: Y
authors: Xiao
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America ; Department of Neurosurgery, University of California San Francisco, San Francisco, California, United States of America.
authors: Shichun
authors: S
authors: Zheng
authors: Department of Pediatrics, St Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.
authors: Leo
authors: L
authors: Kager
authors: Department of Pediatrics, St Anna Children's Hospital, Medical University of Vienna, Vienna, Austria ; Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.
authors: Michael
authors: M
authors: Dworzak
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors: Joseph L
authors: JL
authors: Wiemels
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism*; D059372:Nucleotide Motifs; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D056510:Position-Specific Scoring Matrices; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C089847:E2A-Pbx1 fusion protein