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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

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

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)