title: CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia.
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.
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Gioia
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Trégoat
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dumas
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lagarde
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Prouzet-Mauléon
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.affiliation: CNRS UMR5237, Centre de Recherche de Biochimie Macromoléculaire, Montpellier, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sirvent
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Praloran
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Lippert
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Villacreces
authors.affiliation: Equipe Immunociblage et Radiobiologie en Oncologie, IRCM Institut de Recherche en Cancérologie de Montpellier, INSERM U896-Université Montpellier1-ICM, Montpellier, France.
authors.forename: Wilhem
authors.initials: W
authors.lastname: Leconet
authors.affiliation: Equipe Immunociblage et Radiobiologie en Oncologie, IRCM Institut de Recherche en Cancérologie de Montpellier, INSERM U896-Université Montpellier1-ICM, Montpellier, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Robert
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vigon
authors.affiliation: CNRS UMR5237, Centre de Recherche de Biochimie Macromoléculaire, Montpellier, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Roche
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.affiliation: Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.
authors.forename: Jean-Max
authors.initials: JM
authors.lastname: Pasquet
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004795:Enzyme Stability; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008024:Ligands; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000072377:Syk Kinase; D013997:Time Factors; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D011743:Pyrimidines; D020794:Receptor Protein-Tyrosine Kinases; D000072377:Syk Kinase; D019061:src-Family Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000606896:SYK protein, human; C060902:lyn protein-tyrosine kinase; C067419:CBL protein, human; C498826:nilotinib; C000722289:AXL protein, human
keywords: drug resistance; inhibitors; tyrosine kinase