CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia

J Pathol. 2015 Sep;237(1):14-24. doi: 10.1002/path.4561. Epub 2015 Jun 4.

Abstract

A tyrosine kinase network composed of the TAM receptor AXL and the cytoplasmic kinases LYN and SYK is involved in nilotinib-resistance of chronic myeloid leukaemia (CML) cells. Here, we show that the E3-ubiquitin ligase CBL down-regulation occurring during prolonged drug treatment plays a critical role in this process. Depletion of CBL in K562 cells increases AXL and LYN protein levels, promoting cell resistance to nilotinib. Conversely, forced expression of CBL in nilotinib-resistant K562 cells (K562-rn) dramatically reduces AXL and LYN expression and resensitizes K562-rn cells to nilotinib. A similar mechanism was found to operate in primary CML CD34(+) cells. Mechanistically, the E3-ligase CBL counteracts AXL/SYK signalling, promoting LYN transcription by controlling AXL protein stability. Surprisingly, the role of AXL in resistance was independent of its ligand GAS6 binding and its TK activity, in accordance with a scaffold activity for this receptor being involved in this cellular process. Collectively, our results demonstrate a pivotal role for CBL in the control of a tyrosine kinase network mediating resistance to nilotinib treatment in CML cells.

Keywords: drug resistance; inhibitors; tyrosine kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Axl Receptor Tyrosine Kinase
  • Drug Resistance, Neoplasm*
  • Enzyme Stability
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Ligands
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Pyrimidines / pharmacology*
  • RNA Interference
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction / drug effects*
  • Syk Kinase
  • Time Factors
  • Transfection
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*

Substances

  • Antineoplastic Agents
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrimidines
  • growth arrest-specific protein 6
  • Proto-Oncogene Proteins c-cbl
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • CBL protein, human
  • nilotinib
  • Axl Receptor Tyrosine Kinase
  • AXL protein, human