Telomere loss is accompanied by decreased pool of shelterin proteins TRF2 and RAP1, elevated levels of TERRA and enhanced glycolysis in imatinib-resistant CML cells

Toxicol In Vitro. 2023 Aug:90:105608. doi: 10.1016/j.tiv.2023.105608. Epub 2023 May 4.

Abstract

Telomere length may be maintained by telomerase nucleoprotein complex and shelterin complex, namely TRF1, TRF2, TIN2, TPP1, POT1 and RAP1 proteins and modulated by TERRA expression. Telomere loss is observed during progression of chronic myeloid leukemia (CML) from the chronic phase (CML-CP) to the blastic phase (CML-BP). The introduction of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), has changed outcome for majority of patients, however, a number of patients treated with TKIs may develop drug resistance. The molecular mechanisms underlying this phenomenon are not fully understood and require further investigation. In the present study, we demonstrate that IM-resistant BCR::ABL1 gene-positive CML K-562 and MEG-A2 cells are characterized by decreased telomere length, lowered protein levels of TRF2 and RAP1 and increased expression of TERRA in comparison to corresponding IM-sensitive CML cells and BCR::ABL1 gene-negative HL-60 cells. Furthermore, enhanced activity of glycolytic pathway was observed in IM-resistant CML cells. A negative correlation between a telomere length and advanced glycation end products (AGE) was also revealed in CD34+ cells isolated from CML patients. In conclusion, we suggest that affected expression of shelterin complex proteins, namely TRF2 and RAP1, TERRA levels, and glucose consumption rate may promote telomere dysfunction in IM-resistant CML cells.

Keywords: Advanced glycation end products (AGE); Chronic myeloid leukemia (CML); Glycolysis; Imatinib; Shelterin complex; Telomeres.

MeSH terms

  • Humans
  • Imatinib Mesylate / pharmacology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
  • Shelterin Complex*
  • Telomere / metabolism
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism
  • Telomeric Repeat Binding Protein 2

Substances

  • Shelterin Complex
  • Imatinib Mesylate
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2