title: A novel mechanism for imatinib mesylate (STI571) resistance in CML cell line KT-1: role of TC-PTP in modulating signals downstream from the BCR-ABL fusion protein.
abstract: OBJECTIVE
  Acquired resistance to imatinib mesylate (STI571) in chronic myelogenous leukemia (CML) patients has become a serious clinical problem. We previously established STI571-resistant sublines (designated KTR cells) from the CML cell line KT-1. T cell protein tyrosine phosphatase (TC-PTP) was markedly downregulated in all KTR cells compared to parental KT-1 cells. Therefore, we examined whether the suppression of TC-PTP expression might contribute to imatinib mesylate-resistance in KTR cells.
  
  
  METHODS
  We transduced the nuclear isoform of TC-PTP (TC45) and catalytically inactive TC45-D182A cDNAs into KTR cells by retroviral gene transfer. Subsequently, we analyzed the sensitivity to imatinib mesylate and the status of signaling pathways in the transduced cells.
  
  
  RESULTS
  The overall levels of STAT5 phosphorylation were significantly higher in KTR cells as compared to KT-1 cells, but reconstitution of TC-PTP in KTR cells resulted in a dramatic decrease of STAT5 phosphorylation. Furthermore, STAT5 phosphorylation was ablated by imatinib mesylate in KT-1 cells but remained elevated in KTR cells. In contrast, we observed no difference in BCR-ABL or JAK2 phosphorylation and no difference in activation of other signaling pathways. Importantly, reconstitution of TC-PTP in KTR cells to levels found in parental KT-1 cells restored their sensitivity to imatinib mesylate as monitored by reduced proliferation and increased apoptosis.
  
  
  CONCLUSIONS
  We have demonstrated that forced expression of TC-PTP in imatinib mesylate-resistant KTR cells can restore sensitivity to imatinib mesylate. Our studies indicate that loss of TC-PTP may represent a novel mechanism by which CML cells can acquire imatinib mesylate-resistance.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takatsune
authors.initials: T
authors.lastname: Shimizu
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Miyakawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.forename: Akiko
authors.initials: A
authors.lastname: Kuribara
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kizaki
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D008894:Milk Proteins / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D001549:Benzamides; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases