title: Quantitative proteomic analysis reveals maturation as a mechanism underlying glucocorticoid resistance in B lineage ALL and re-sensitization by JNK inhibition.
abstract: Glucocorticoid (GC) resistance is a continuing clinical problem in childhood acute lymphoblastic leukaemia (ALL) but the underlying mechanisms remain unclear. A proteomic approach was used to compare profiles of the B-lineage ALL GC-sensitive cell line, PreB 697, and its GC-resistant sub-line, R3F9, pre- and post-dexamethasone exposure. PAX5, a transcription factor critical to B-cell development was differentially regulated in the PreB 697 compared to the R3F9 cell line in response to GC. PAX5 basal protein expression was less in R3F9 compared to its GC-sensitive parent and confirmed to be lower in other GC-resistant sub-lines of Pre B 697 and was associated with a decreased expression of the PAX5 transcriptional target, CD19. Gene set enrichment analysis showed that increasing GC-resistance was associated with differentiation from preB-II to an immature B-lymphocyte stage. GC-resistant sub-lines were shown to have higher levels of phosphorylated JNK compared to the parent line and JNK inhibition caused re-sensitization to GC. Exploiting this maturation may be key to overcoming GC resistance and targeting signalling pathways linked to the maturation state, such as JNK, may be a novel approach.
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Lindsay
authors: L
authors: Nicholson
authors: Stem Cell and Leukaemia Proteomics Laboratory, School of Cancer and Enabling Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors: Caroline A
authors: CA
authors: Evans
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Elizabeth
authors: E
authors: Matheson
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Lynne
authors: L
authors: Minto
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Christopher
authors: C
authors: Keilty
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Maryna
authors: M
authors: Sanichar
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Marian
authors: M
authors: Case
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Claire
authors: C
authors: Schwab
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Daniel
authors: D
authors: Williamson
authors: Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors: Johannes
authors: J
authors: Rainer
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Christine J
authors: CJ
authors: Harrison
authors: Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors: Reinhard
authors: R
authors: Kofler
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Andrew G
authors: AG
authors: Hall
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Christopher P F
authors: CP
authors: Redfern
authors: Stem Cell and Leukaemia Proteomics Laboratory, School of Cancer and Enabling Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors: Anthony D
authors: AD
authors: Whetton
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Julie A E
authors: JA
authors: Irving
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005091:Exons / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D040901:Proteomics / Q000379:methods*; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D047428:Protein Kinase Inhibitors; D003907:Dexamethasone; D048670:MAP Kinase Kinase 4
keywords: B cell differentiation; JNK signalling; childhood acute lymphoblastic leukaemia; glucocorticoid resistance; iTRAQ proteomics