Secretion of IL-1β from imatinib-resistant chronic myeloid leukemia cells contributes to BCR-ABL mutation-independent imatinib resistance

FEBS Lett. 2016 Feb;590(3):358-68. doi: 10.1002/1873-3468.12057. Epub 2016 Jan 25.

Abstract

Some cases of chronic myelogenous leukemia are resistant to tyrosine kinase inhibitors (TKIs) independently of mutation in BCR-ABL, but the detailed mechanism underlying this resistance has not yet been elucidated. In this study, we generated a TKI-resistant CML cell line, K562R, that lacks a mutation in BCR-ABL. Interleukin-1β (IL-1β) was more highly expressed in K562R than in the parental cell line K562S, and higher levels of IL-1β contributed to the imatinib resistance of K562R. In addition, IL-1β secreted from K562R cells affected stromal cell production of CXCL11, which in turn promoted migration of K562R cells into the stroma. Thus, elevated IL-1β production from TKI-resistant K562R cells may contribute to TKI resistance by increasing cell viability and promoting cell migration.

Keywords: BCR-ABL; chronic myeloid leukemia; resistance; tyrosine kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line
  • Cell Movement / drug effects
  • Chemokine CXCL11 / genetics
  • Chemokine CXCL11 / metabolism
  • Coculture Techniques
  • Culture Media, Conditioned / metabolism
  • Drug Resistance, Neoplasm*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imatinib Mesylate / pharmacology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Mutation
  • Neoplasm Proteins / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Stromal Cells / metabolism
  • Up-Regulation*

Substances

  • Antineoplastic Agents
  • BCR-ABL1 fusion protein, human
  • CXCL11 protein, human
  • Chemokine CXCL11
  • Culture Media, Conditioned
  • IL1B protein, human
  • Interleukin-1beta
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl