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


RESULTS
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.


CONCLUSIONS
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.
Nodality Inc., South San Francisco, California, United States of America.
Adam L
AL
Palazzo
Erik
E
Evensen
Ying-Wen
YW
Huang
Alessandra
A
Cesano
Garry P
GP
Nolan
Wendy J
WJ
Fantl
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D020543:Proteome / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D059010:Single-Cell Analysis; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D014408:Biomarkers, Tumor; D020543:Proteome; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D014740:Vidarabine; C024352:fludarabine