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

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T1 - Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation.

AU - Håkansson, Petra

AU - Nilsson, Björn

AU - Andersson, Anna

AU - Lassen, Carin

AU - Gullberg, Urban

AU - Fioretos, Thoas

N1 - (c) 2008 Wiley-Liss, Inc.

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - Benzamides

KW - Biomarkers, Tumor

KW - Blotting, Northern

KW - Blotting, Western

KW - Feedback, Physiological

KW - Fusion Proteins, bcr-abl

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Leukemic

KW - Humans

KW - Imatinib Mesylate

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive

KW - Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative

KW - Oligonucleotide Array Sequence Analysis

KW - Philadelphia Chromosome

KW - Piperazines

KW - Protein Kinase Inhibitors

KW - Protein-Tyrosine Kinases

KW - Pyrimidines

KW - Signal Transduction

KW - Transcription, Genetic

KW - Tumor Cells, Cultured

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/gcc.20528

DO - 10.1002/gcc.20528

M3 - Article

C2 - 18181176

VL - 47

SP - 267

EP - 275

JO - Genes, Chromosomes and Cancer

JF - Genes, Chromosomes and Cancer

SN - 1045-2257

IS - 4

ER -