The pro-metastasis tyrosine phosphatase, PRL-3 (PTP4A3), is a novel mediator of oncogenic function of BCR-ABL in human chronic myeloid leukemia

Mol Cancer. 2012 Sep 21:11:72. doi: 10.1186/1476-4598-11-72.

Abstract

Background: Resistance to tyrosine kinase inhibitors (TKIs) remains a challenge in management of patients with chronic myeloid leukemia (CML). A better understanding of the BCR-ABL signalling network may lead to better therapy.

Findings: Here we report the discovery of a novel downstream target of BCR-ABL signalling, PRL-3 (PTP4A3), an oncogenic tyrosine phosphatase. Analysis of CML cancer cell lines and CML patient samples reveals the upregulation of PRL-3. Inhibition of BCR-ABL signalling either by Imatinib or by RNAi silencing BCR-ABL reduces PRL-3 and increases cleavage of PARP. In contrast, the amount of PRL-3 protein remains constant or even increased in response to Imatinib treatment in drug resistant cells expressing P210 T315I. Finally, analysis with specific shRNA shows PRL-3 involvement in the proliferation and self-renewal of CML cells.

Conclusions: These data support a role for PRL-3 in BCR-ABL signalling and CML biology and may be a potential therapeutic target downstream of BCR-ABL in TKI resistant mutant cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Benzamides
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Drug Resistance, Neoplasm / genetics
  • Fusion Proteins, bcr-abl / genetics*
  • Gene Expression
  • Gene Expression Regulation, Leukemic
  • Gene Silencing
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Neoplasm Metastasis / genetics
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics*
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / genetics*
  • Pyrimidines / pharmacology
  • STAT Transcription Factors / metabolism
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Benzamides
  • Neoplasm Proteins
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • STAT Transcription Factors
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • PTP4A3 protein, human
  • Protein Tyrosine Phosphatases