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

Håkansson, Petra LU ; Nilsson, Björn LU ; Andersson, Anna LU ; Lassen, Carin LU ; Gullberg, Urban LU and Fioretos, Thoas LU (2008) In Genes, Chromosomes and Cancer 47(4). p.267-275
Abstract

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... (More)

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.

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keywords
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
in
Genes, Chromosomes and Cancer
volume
47
issue
4
pages
9 pages
publisher
John Wiley & Sons
external identifiers
  • pmid:18181176
  • wos:000253519900001
  • scopus:40049090339
ISSN
1045-2257
DOI
10.1002/gcc.20528
language
English
LU publication?
yes
id
25309cbf-cab0-4251-84dc-b89ca94f1c69 (old id 1021553)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18181176?dopt=Abstract
date added to LUP
2008-02-08 16:05:17
date last changed
2017-09-03 03:50:19
@article{25309cbf-cab0-4251-84dc-b89ca94f1c69,
  abstract     = {<p>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.</p>},
  author       = {Håkansson, Petra and Nilsson, Björn and Andersson, Anna and Lassen, Carin and Gullberg, Urban and Fioretos, Thoas},
  issn         = {1045-2257},
  keyword      = {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},
  language     = {eng},
  number       = {4},
  pages        = {267--275},
  publisher    = {John Wiley & Sons},
  series       = {Genes, Chromosomes and Cancer},
  title        = {Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation.},
  url          = {http://dx.doi.org/10.1002/gcc.20528},
  volume       = {47},
  year         = {2008},
}