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Tytuł pozycji:

Constitutive Activation of the B Cell Receptor Underlies Dysfunctional Signaling in Chronic Lymphocytic Leukemia.

Tytuł:
Constitutive Activation of the B Cell Receptor Underlies Dysfunctional Signaling in Chronic Lymphocytic Leukemia.
Autorzy:
Ziegler CGK; ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: carly_.
Kim J; ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Piersanti K; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Oyler-Yaniv A; ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Physics Department, Ben Gurion University, Beer-Sheva, Israel.
Argyropoulos KV; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
van den Brink MRM; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Palomba ML; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Altan-Bonnet N; National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Altan-Bonnet G; ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: .
Źródło:
Cell reports [Cell Rep] 2019 Jul 23; Vol. 28 (4), pp. 923-937.e3.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: [Cambridge, MA] : Cell Press, c 2012-
MeSH Terms:
Signal Transduction*/drug effects
Leukemia, Lymphocytic, Chronic, B-Cell/*immunology
Receptors, Antigen, B-Cell/*metabolism
Adult ; Aged ; Aged, 80 and over ; Biophysical Phenomena ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Feedback, Physiological/drug effects ; Female ; Humans ; Male ; Middle Aged ; Models, Biological ; Phosphoprotein Phosphatases/antagonists & inhibitors ; Phosphoprotein Phosphatases/metabolism ; Protein Kinases/metabolism ; Single-Cell Analysis ; Small Molecule Libraries/pharmacology
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Grant Information:
ZIA BC011726 United States ImNIH Intramural NIH HHS; ZIA BC011726-03 United States ImNIH Intramural NIH HHS; T32 GM007753 United States GM NIGMS NIH HHS; P30 CA008748 United States CA NCI NIH HHS; Z99 CA999999 United States ImNIH Intramural NIH HHS; U54 CA148967 United States CA NCI NIH HHS; R01 AI083408 United States AI NIAID NIH HHS; ZIA BC011726-02 United States ImNIH Intramural NIH HHS
Contributed Indexing:
Keywords: B cell; B cell receptor; BCR; CLL; cell signaling; chronic lymphocytic leukemia; clinical classification; computational modelling; hysteresis; receptor clustering; super-resolution microscopy; systems immunology
Substance Nomenclature:
0 (Enzyme Inhibitors)
0 (Receptors, Antigen, B-Cell)
0 (Small Molecule Libraries)
EC 2.7.- (Protein Kinases)
EC 3.1.3.16 (Phosphoprotein Phosphatases)
Entry Date(s):
Date Created: 20190725 Date Completed: 20200824 Latest Revision: 20210404
Update Code:
20240105
PubMed Central ID:
PMC8018719
DOI:
10.1016/j.celrep.2019.06.069
PMID:
31340154
Czasopismo naukowe
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.
(Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

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