Association of reactive oxygen species-mediated signal transduction with in vitro apoptosis sensitivity in chronic lymphocytic leukemia B cells

• Published in: PloS one Vol. 6; no. 10; p. e24592
• Main Authors: Palazzo, Adam L, Evensen, Erik, Huang, Ying-Wen, Cesano, Alessandra, Nolan, Garry P, Fantl, Wendy J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.10.2011; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Analysis; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; B cells; B-cell receptor; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biology; Biomarkers, Tumor - metabolism; Cell Line, Tumor; Cellular signal transduction; Chemical compounds; Chemotherapy; Chronic lymphocytic leukemia; Cytometry; Female; Flow cytometry; Fludarabine; Health aspects; Humans; Hydrogen; Hydrogen peroxide; Hydrogen Peroxide - pharmacology; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphatic leukemia; Lymphocyte receptors; Lymphocytes B; Lymphocytic leukemia; Male; Malignancy; Medicine; Middle Aged; Modulators; Mutation; Oxygen; Pharmacology; Phosphatases; Phosphorylation; Phosphorylation - drug effects; Protein-tyrosine-phosphatase; Proteins; Proteome - drug effects; Proteome - immunology; Proteome - metabolism; Reactive oxygen species; Reactive Oxygen Species - pharmacology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; Signaling; Single-Cell Analysis; Statistical analysis; Statistical methods; Thermal resistance; Tyrosine; Vidarabine - analogs & derivatives; Vidarabine - pharmacology; Palo Alto California; South San Francisco California; California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0024592

Chronic lymphocytic leukemia (CLL) is a B cell malignancy with a variable clinical course and unpredictable response to therapeutic agents. Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in signaling biology in the context of molecular changes occurring in malignancies. In this study SCNP was used to identify proteomic profiles associated with in vitro apoptotic responsiveness of CLL B cells to fludarabine, as a basis for ultimately linking these with clinical outcome. SCNP was used to quantify modulated-signaling of B cell receptor (BCR) network proteins and in vitro F-ara-A mediated apoptosis in 23 CLL samples. Of the modulators studied the reactive oxygen species, hydrogen peroxide (H₂O₂), a known intracellular second messenger and a general tyrosine phosphatase inhibitor stratified CLL samples into two sub-groups based on the percentage of B cells in a CLL sample with increased phosphorylation of BCR network proteins. Separately, in the same patient samples, in vitro exposure to F-ara-A also identified two sub-groups with B cells showing competence or refractoriness to apoptotic induction. Statistical analysis showed that in vitro F-ara-A apoptotic proficiency was highly associated with the proficiency of CLL B cells to undergo H₂O₂-augmented signaling. This linkage in CLL B cells among the mechanisms governing chemotherapy-induced apoptosis increased signaling of BCR network proteins and a likely role of phosphatase activity suggests a means of stratifying patients for their response to F-ara-A based regimens. Future studies will examine the clinical applicability of these findings and also the utility of this approach in relating mechanism to function of therapeutic agents.