Premium
CBL controls a tyrosine kinase network involving AXL , SYK and LYN in nilotinib‐resistant chronic myeloid leukaemia
Author(s) -
Gioia Romain,
Trégoat Claire,
Dumas PierreYves,
Lagarde Valérie,
ProuzetMauléon Valérie,
Desplat Vanessa,
Sirvent Audrey,
Praloran Vincent,
Lippert Eric,
Villacreces Arnaud,
Leconet Wilhem,
Robert Bruno,
Vigon Isabelle,
Roche Serge,
Mahon FrançoisXavier,
Pasquet JeanMax
Publication year - 2015
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4561
Subject(s) - nilotinib , lyn , syk , gas6 , tyrosine kinase , ubiquitin ligase , cancer research , axl receptor tyrosine kinase , k562 cells , chemistry , microbiology and biotechnology , receptor tyrosine kinase , tyrosine kinase inhibitor , kinase , biology , signal transduction , medicine , cell , biochemistry , ubiquitin , jak stat signaling pathway , cancer , gene
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. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.