title: Transcriptional suppression of BACH2 by the Bcr-Abl oncoprotein is mediated by PAX5.
abstract: Bach2 is a lymphoid-specific transcription factor with a prominent role in B-cell development and apoptosis-induction in response to oxidative stress. We previously showed that Bach2 is downregulated in chronic myeloid leukaemia (CML), and here we demonstrate the mechanism by which Bcr-Abl mediates this phenomenon. We have cloned a 3.9 Kb genomic DNA fragment upstream of the transcription initiation site, and delineated the core and proximal BACH2 promoter regions. Transient BCR-ABL expression led to significant reduction in BACH2 promoter activity and this effect was dependent on the kinase function of the oncoprotein. Sequential deletions disclosed several regulatory elements within the promoter region, as well as within BACH2 exonic sequences. Analysis of these elements and transient transfection assays led to the identification of the Pax5 transcription factor as a potent trans-activator of BACH2, whose effect is predominantly mediated through occupation of a binding site on the BACH2 promoter, as demonstrated by both in vitro and in vivo experiments. Overall, our data show that Pax5 functions as an intermediate effector in the Bcr-Abl-mediated transcriptional repression of BACH2. The current results, combined with previous reports, establish Pax5 and Bach2 as transcriptional targets of Bcr-Abl, whose downregulation may contribute to lymphoid blast crisis of CML.
authors.affiliation: Department of Haematology, Centre for Cancer Biology, SA Pathology University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: D A
authors.initials: DA
authors.lastname: Casolari
authors.forename: M
authors.initials: M
authors.lastname: Makri
authors.forename: C
authors.initials: C
authors.lastname: Yoshida
authors.forename: A
authors.initials: A
authors.lastname: Muto
authors.forename: K
authors.initials: K
authors.lastname: Igarashi
authors.forename: J V
authors.initials: JV
authors.lastname: Melo
mesh_terms: D000107:Acetylation; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D001752:Blast Crisis / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D024202:Electrophoretic Mobility Shift Assay; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D006657:Histones; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D008156:Luciferases; D016044:Fusion Proteins, bcr-abl