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

In English

Författare

Summary, in 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.

Publiceringsår

2008

Språk

Engelska

Sidor

267-275

Publikation/Tidskrift/Serie

Genes, Chromosomes and Cancer

Volym

47

Issue

4

Dokumenttyp

Artikel i tidskrift

Förlag

John Wiley & Sons Inc.

Ämne

  • Medical Genetics
  • Hematology

Nyckelord

  • 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

Status

Published

Forskningsgrupp

  • Hematogenomics
  • Transcriptional mechanisms for the Wilms’ tumor gene 1 (WT1) oncoprotein

ISBN/ISSN/Övrigt

  • ISSN: 1045-2257