association of reactive oxygen species-mediated signal transduction with in vitro apoptosis sensitivity in chronic lymphocytic leukemia b cells活性氧species-mediated协会与体外细胞凋亡信号转导在慢性淋巴细胞白血病(b细胞的敏感性.pdf

Association of Reactive Oxygen Species-Mediated Signal Transduction with In Vitro Apoptosis Sensitivity in Chronic Lymphocytic Leukemia B Cells 1. 1. 1 1 2 Adam L. Palazzo , Erik Evensen , Ying-Wen Huang , Alessandra Cesano , Garry P. Nolan , Wendy J. Fantl1,2* 1 Nodality Inc., South San Francisco, California, United States of America, 2 Baxter Laboratory for Stem Cell Biology and Department of Microbiology and Immunology, Stanford University, Palo Alto, California, United States of America Abstract Background: 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. Methodology/Principal Finding: 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 (H O ), a known intracellular second messenger and a general tyrosine phosphatase inhibitor stratified CLL 2 2 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