Identification of prognostic protein biomarkers in childhood acute lymphoblastic leukemia (ALL)

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), cofilin1, voltage-dependent anion-channel protein1 (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.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (257 K)Download as PowerPoint slideResearch highlights► We performed proteomic analysis on PRED-sensitive and resistant ALL cell lines. ► Several differentially expressed proteins were identified in these cells. ► PCNA was validated in paired patient bone marrows (at diagnosis and after PRED). ► PCNA was identified to have prognostic value.