title: BCR/ABL1 and BCR are under the transcriptional control of the MYC oncogene.
abstract: BACKGROUND
  Chronic Myeloid Leukaemia (CML) is caused by the BCR/ABL1 fusion gene. Both the presence and the levels of BCR/ABL1 expression seem to be critical for CML progression from chronic phase (CP) to blast crisis (BC). After the oncogenic translocation, the BCR/ABL1 gene is under the transcriptional control of BCR promoter but the molecular mechanisms involved in the regulation of oncogene expression are mostly unknown.
  
  
  METHODS
  A region of 1443bp of the functional BCR promoter was studied for transcription factor binding sites through in-silico analysis and Chromatin Immunoprecipitation experiments. BCR and BCR/ABL1 expression levels were analysed in CML cell lines after over-expression or silencing of MYC transcription factor. A luciferase reporter assay was used to confirm its activity on BCR promoter.
  
  
  RESULTS
  In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels. Accordingly, silencing of MYC expression in various BCR/ABL1 positive cell lines causes significant downregulation of BCR and BCR/ABL1, which consequently leads to decreased proliferation and induction of cell death.
  
  
  CONCLUSIONS
  Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer. Since MYC is frequently over-expressed in BC, this phenomenon could play a critical role in BCR/ABL1 up-regulation and blast aggressiveness acquired during CML evolution.
authors.affiliation: Department of Health Sciences, University of Milano Bicocca, Monza, Italy. niteshsharma700@gmail.com.
authors.forename: Nitesh
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Health Sciences, University of Milano Bicocca, Monza, Italy. vera.magistroni@unimib.it.
authors.forename: Vera
authors.initials: V
authors.lastname: Magistroni
authors.affiliation: Department of Health Sciences, University of Milano Bicocca, Monza, Italy. rocco.piazza@unimib.it.|Division of Haematology, San Gerardo Hospital, Monza, Italy. rocco.piazza@unimib.it.
authors.forename: Rocco
authors.initials: R
authors.lastname: Piazza
authors.affiliation: Department of Bioscience and Biotechnology, University of Milano Bicocca, Milano, Italy. stefania.citterio@unimib.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Citterio
authors.affiliation: Department of Health Sciences, University of Milano Bicocca, Monza, Italy. kata08@live.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mezzatesta
authors.affiliation: Department of Health Sciences, University of Milano Bicocca, Monza, Italy. praveenkhandelwal49@gmail.com.
authors.forename: Praveen
authors.initials: P
authors.lastname: Khandelwal
authors.affiliation: Department of Health Sciences, University of Milano Bicocca, Monza, Italy. alessandra.pirola@unimib.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pirola
authors.affiliation: Department of Health Sciences, University of Milano Bicocca, Monza, Italy. carlo.gambacorti@unimib.it.|Division of Haematology, San Gerardo Hospital, Monza, Italy. carlo.gambacorti@unimib.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051562:Proto-Oncogene Proteins c-bcr / Q000737:chemistry / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C106465:MNT protein, human; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl; D051562:Proto-Oncogene Proteins c-bcr