Transcriptional suppression of BACH2 by the Bcr-Abl oncoprotein is mediated by PAX5

D. A. Casolari, M. Makri, C. Yoshida, A. Muto, K. Igarashi, J. V. Melo

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)409-415
Number of pages7
JournalLeukemia
Volume27
Issue number2
DOIs
Publication statusPublished - 2013 Feb

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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