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Published on: October 11, 2018
Identification of prognostic protein biomarkers in childhood acute lymphoblastic leukemia (ALL)
Nan Jiang1, Shirley Kow Yin Kham, Grace Shimin Koh
1Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Insights
Early response to prednisolone (PRED) treatment predicts outcomes in childhood acute lymphoblastic leukemia (ALL). Proliferating cell nuclear antigen (PCNA) is identified as a key prognostic biomarker for PRED response in ALL patients.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Early response to prednisolone (PRED) is a critical prognostic factor in childhood acute lymphoblastic leukemia (ALL).
- Identifying reliable biomarkers for treatment response is crucial for optimizing ALL patient outcomes.
- Proteomic approaches offer potential for discovering novel prognostic markers in leukemia.
Purpose of the Study:
- To identify protein biomarkers predicting prednisolone response in childhood ALL.
- To discover regulators of prednisolone-induced apoptosis in ALL cell lines.
- To validate potential biomarkers in patient samples for clinical utility.
Main Methods:
- Utilized proteomic analysis (2D gel electrophoresis, MALDI-TOF/TOF MS) on ALL cell lines (REH, 697, Sup-B15, RS4;11) treated with PRED.
- Validated differentially expressed proteins, including proliferating cell nuclear antigen (PCNA), using Western blot.
- Analyzed PCNA expression in paired bone marrow samples from newly diagnosed ALL patients (Day 0 and Day 8 of PRED treatment).
Main Results:
- Identified 77 and 17 differentially expressed protein spots in PRED-sensitive and PRED-resistant ALL cell lines, respectively.
- PCNA was significantly differentially expressed and validated as a potential prognostic marker.
- ROC curve analysis demonstrated PCNA's high predictive value for PRED response in ALL patients (AUC=0.81, p=0.007), independent of molecular subtype.
Conclusions:
- PCNA is a promising universal prognostic biomarker for predicting prednisolone response in childhood ALL.
- Early assessment of PCNA levels could aid in tailoring treatment strategies for ALL patients.
- Proteomic discovery of PCNA highlights its role in cell cycle regulation and survival control relevant to leukemia treatment.
Abstract:
Early response to 7 days of prednisolone (PRED) treatment is one of the important prognostic factors in predicting eventual outcome in childhood acute lymphoblastic leukemia (ALL). Using proteomic tools and clinically important leukemia cell lines (REH, 697, Sup-B15, RS4; 11), we have identified potential prognostic protein biomarkers as well as discovered promising regulators of PRED-induced apoptosis. After treatment with PRED, the four cell lines can be separated into resistant (REH) and sensitive (697, Sup-B15, RS4;11). Two dimensional gel electrophoresis (2-DE) and MALDI-TOF/TOF MS identified 77 and 17 significantly differentially expressed protein spots (p<0.05) in PRED-sensitive and PRED-resistant cell lines respectively. Several of these were validated by Western blot including proliferating cell nuclear antigen (PCNA), cofilin 1, voltage-dependent anion-channel protein 1 (VDAC1) and proteasome activator subunit 2 (PA28β). PCNA is a promising protein because of its important roles both in cell cycle regulation and survival control. We subsequently validated PCNA in 43 paired bone marrow samples from children with newly diagnosed ALL (Day 0) and 7 days after PRED treatment (Day 8). ROC curve analysis confirmed that PCNA was highly predictive of PRED response in patients (AUC=0.81, p=0.007) and most interestingly, independent of the molecular subtype, providing a promising universal prognostic marker.
