Constitutive activation of the B cell receptor underlies dysfunctional signaling in chronic lymphocytic leukemia Journal Article

  

Authors:	Ziegler, C. G. K.; Kim, J.; Piersanti, K.; Oyler-Yaniv, A.; Argyropoulos, K. V.; van den Brink, M. R. M.; Palomba, M. L.; Altan-Bonnet, N.; Altan-Bonnet, G.
Article Title:	Constitutive activation of the B cell receptor underlies dysfunctional signaling in chronic lymphocytic leukemia
Abstract:	In cancer biology, the functional interpretation of genomic alterations is critical to achieve the promise of genomic profiling in the clinic. For chronic lymphocytic leukemia (CLL), a heterogeneous disease of B-lymphocytes maturing under constitutive B cell receptor (BCR) stimulation, the functional role of diverse clonal mutations remains largely unknown. Here, we demonstrate that alterations in BCR signaling dynamics underlie the progression of B cells toward malignancy. We reveal emergent dynamic features—bimodality, hypersensitivity, and hysteresis—in the BCR signaling pathway of primary CLL B cells. These signaling abnormalities in CLL quantitatively derive from BCR clustering and constitutive signaling with positive feedback reinforcement, as demonstrated through single-cell analysis of phospho-responses, computational modeling, and super-resolution imaging. Such dysregulated signaling segregates CLL patients by disease severity and clinical presentation. These findings provide a quantitative framework and methodology to assess complex and heterogeneous leukemia pathology and to inform therapeutic strategies in parallel with genomic profiling. © 2019 The Author(s) Using phospho-flow cytometry and computational modeling, Ziegler et al. find that B cell receptor clustering and positive feedback through SYK and LYN drive signaling hypersensitivity, bistability, and hysteresis in chronic lymphocytic leukemic B cells. Super-resolution microscopy confirms membrane auto-aggregation in leukemic B cells, and variability in signaling dysfunction predicts disease severity. © 2019 The Author(s)
Keywords:	cll; b cell; cell signaling; chronic lymphocytic leukemia; clinical classification; Systems Immunology; hysteresis; bcr; b cell receptor; computational modelling; receptor clustering; super-resolution microscopy
Journal Title:	Cell Reports
Volume:	28
Issue:	4
ISSN:	2211-1247
Publisher:	Cell Press
Date Published:	2019-07-23
Start Page:	923
End Page:	937.e3
Language:	English
DOI:	10.1016/j.celrep.2019.06.069
PROVIDER:	scopus
PUBMED:	31340154
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85068779371&doi=10.1016%2fj.celrep.2019.06.069&partnerID=40&md5=331a80d82f6b3096e34ea3e552607f71
Notes:	Source: Scopus