Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance

Abstract

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 casecontrol 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. Valosincontaining 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 (P 25 -P 75 ) was 0.15 (0.11-0.28) in PGR and 0.34 (0.14-0.99) in PPR patients (P ¼ 0.04). We conclude that high VCP expression is associated with poor prednisone response in childhood ALL patients.

Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000

“…[68][69][70][71][72][73][74][75][76][77][78] While in the era of genomics the number of papers in the field of leukemia has risen amazingly, it remains difficult to filter out the information, which can be used for improved treatment quality and better prevention of disease recurrence. Certainly one prerequisite is reproducibility of data, and thus, uniform approaches are needed if such techniques shall be used routinely in clinical diagnostics and for risk assessment.…”

Deficiency of the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr virus (EBV) induced mononucleosis and promotes lymphoma development

“…VCP has a pro-survival function, demonstrated both in yeast and in mammalian cells [46,47]. Elevated VCP levels were found to correlate with increased incidence of metastasis in prostate cancer, esophageal carcinoma, and leukemia [48,49]. In several cell types expression of mutant VCP or downregulation of VCP led to apoptosis [47].…”

Effects of gene polymorphisms in the endoplasmic reticulum stress pathway on clinical outcomes of chemoradiotherapy in Chinese patients with nasopharyngeal carcinoma

“…The expression of VCP has been found to be related to the pathological state and clinical outcome of human tumors such as childhood acute lymphoblastic leukemia [25] . The results from our study indicated that the C allele of VCP rs2074549 was significantly associated with the risk of occurrence of grade 3+ myelosuppression directly after CRT in NPC patients (P=0.008), particularly in the subgroup of patients at stage T3 and T4 (P=0.003).…”