Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance.
The response to initial glucocorticoid therapy in childhood acute lymphoblastic leukaemia (ALL) reliably predicts the response to multiagent chemotherapy. Patients resistant to glucocorticoids (prednisone poor responders (PPR)) have a poorer event-free survival compared to glucocorticoid-sensitive patients (prednisone good responders (PGR)). A case-control study was performed to investigate differential protein expression in leukaemic blasts from PGR and PPR childhood ALL patients. Two-dimensional gel electrophoresis (2-DE) was used for an unsupervised screening and surface enhanced laser desorption/ionisation-time of flight mass spectrometry (SELDI-TOF MS) for the characterisation of protein spots. In difference maps of average gels for the proteomes of each responder group, differentially expressed proteins were identified after tryptic digestion and spotting onto H4-SELDI-TOF-MS chips. Proteins overexpressed in PPR were Catalase, RING finger protein 22 alpha, Valosin-containing protein (VCP) and a G-protein-coupled receptor. Proteins overexpressed in PGR were protein kinase C and malate dehydrogenase. Valosin-containing protein was chosen for validation and quantification by Western blot analysis in a second case-control group of ALL patients. In this second independent cohort, median VCP expression (P25-P75) was 0.15 (0.11-0.28) in PGR and 0.34 (0.14-0.99) in PPR patients (P = 0.04). We conclude that high VCP expression is associated with poor prednisone response in childhood ALL patients.
Lauten
M
M
Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology and Oncology, University of Freiburg, Freiburg, Germany. melchior.lauten@uniklinik-freiburg.de
Schrauder
A
A
Kardinal
C
C
Harbott
J
J
Welte
K
K
Schlegelberger
B
B
Schrappe
M
M
von Neuhoff
N
N
D000251:Adenosine Triphosphatases; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D016022:Case-Control Studies; D002374:Catalase / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008291:Malate Dehydrogenase / Q000096:biosynthesis; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D011241:Prednisone / Q000494:pharmacology / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000096:biosynthesis; D020543:Proteome / Q000032:analysis*; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D012680:Sensitivity and Specificity; D000074405:Valosin Containing Protein
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D005938:Glucocorticoids; D020543:Proteome; D043562:Receptors, G-Protein-Coupled; D008291:Malate Dehydrogenase; D002374:Catalase; D011493:Protein Kinase C; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; D011241:Prednisone