Regulative Loop between β-catenin and Protein Tyrosine Receptor Type γ in Chronic Myeloid Leukemia

Int J Mol Sci. 2020 Mar 26;21(7):2298. doi: 10.3390/ijms21072298.


Protein tyrosine phosphatase receptor type γ (PTPRG) is a tumor suppressor gene, down-regulated in Chronic Myeloid Leukemia (CML) cells by the hypermethylation of its promoter region. β-catenin (CTNNB1) is a critical regulator of Leukemic Stem Cells (LSC) maintenance and CML proliferation. This study aims to demonstrate the antagonistic regulation between β-catenin and PTPRG in CML cells. The specific inhibition of PTPRG increases the activation state of BCR-ABL1 and modulates the expression of the BCR-ABL1- downstream gene β-Catenin. PTPRG was found to be capable of dephosphorylating β-catenin, eventually causing its cytosolic destabilization and degradation in cells expressing PTPRG. Furthermore, we demonstrated that the increased expression of β-catenin in PTPRG-negative CML cell lines correlates with DNA (cytosine-5)-methyl transferase 1 (DNMT1) over-expression, which is responsible for PTPRG promoter hypermethylation, while its inhibition or down-regulation correlates with PTPRG re-expression. We finally confirmed the role of PTPRG in regulating BCR-ABL1 and β-catenin phosphorylation in primary human CML samples. We describe here, for the first time, the existence of a regulative loop occurring between PTPRG and β-catenin, whose reciprocal imbalance affects the proliferation kinetics of CML cells.

Keywords: 5-azacytidine; DNMT; PTPRG; chronic myeloid leukemia; methylation; tumor suppressor; tyrosine phosphatase; β-catenin.

MeSH terms

  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • DNA Methylation
  • Down-Regulation
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Promoter Regions, Genetic
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / genetics*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / metabolism
  • Tumor Cells, Cultured
  • beta Catenin / genetics*
  • beta Catenin / metabolism


  • BCR-ABL1 fusion protein, human
  • CTNNB1 protein, human
  • beta Catenin
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • Fusion Proteins, bcr-abl
  • PTPRG protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5