Menu

Javascript is not activated in your browser. This website needs javascript activated to work properly.
You are here

Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation.

Author:
  • Petra Håkansson
  • Björn Nilsson
  • Anna Andersson
  • Carin Lassen
  • Urban Gullberg
  • Thoas Fioretos
Publishing year: 2008
Language: English
Pages: 267-275
Publication/Series: Genes, Chromosomes and Cancer
Volume: 47
Issue: 4
Document type: Journal article
Publisher: John Wiley & Sons

Abstract english

Philadelphia (Ph) chromosome-positive leukemia is characterized by the BCR/ABL1 fusion protein that affects a wide range of signal transduction pathways. The knowledge about its downstream target genes is, however, still quite limited. To identify novel BCR/ABL1-regulated genes we used global gene expression profiling of several Ph-positive and Ph-negative cell lines treated with imatinib. Following imatinib treatment, the Ph-positive cells showed decreased growth, viability, and reduced phosphorylation of BCR/ABL1 and STAT5. In total, 142 genes were identified as being dependent on BCR/ABL1-mediated signaling, mainly including genes involved in signal transduction, e.g. the JAK/STAT, MAPK, TGFB, and insulin signaling pathways, and in regulation of metabolism. Interestingly, BCR/ABL1 was found to activate several genes involved in negative feedback regulation (CISH, SOCS2, SOCS3, PIM1, DUSP6, and TNFAIP3), which may act to indirectly suppress the tumor promoting effects exerted by BCR/ABL1. In addition, several genes identified as deregulated upon BCR/ABL1 expression could be assigned to the TGFB and NFkB signaling pathways, as well as to reflect the metabolic adjustments needed for rapidly growing cells. Apart from providing important pathogenetic insights into BCR/ABL1-mediated leukemogenesis, the present study also provides a number of pathways/individual genes that may provide attractive targets for future development of targeted therapies. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Keywords

  • Medical Genetics
  • Hematology
  • Benzamides
  • Biomarkers, Tumor
  • Blotting, Northern
  • Blotting, Western
  • Feedback, Physiological
  • Fusion Proteins, bcr-abl
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
  • Oligonucleotide Array Sequence Analysis
  • Philadelphia Chromosome
  • Piperazines
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Pyrimidines
  • Signal Transduction
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Journal Article
  • Research Support, Non-U.S. Gov't

Other

Published
  • Hematogenomics
  • Transcriptional mechanisms for the Wilms’ tumor gene 1 (WT1) oncoprotein
  • ISSN: 1045-2257
Thoas Fioretos
E-mail: thoas.fioretos [at] med.lu.se

Principal investigator

Division of Clinical Genetics

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66