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Constitutive Activation of BCR Explains Dysfunctional Signaling in Chronic Lymphocytic Leukemia

58 Pages Posted: 5 Mar 2019 Sneak Peek Status: Published

See all articles by Carly G. K. Ziegler

Carly G. K. Ziegler

Memorial Sloan Kettering Cancer Center - ImmunoDynamics Group

Joel Kim

Memorial Sloan Kettering Cancer Center - ImmunoDynamics Group

Kelly Piersanti

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

Alon Oyler-Yaniv

Memorial Sloan Kettering Cancer Center - ImmunoDynamics Group

Kimon V. Argyropoulos

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

Marcel van den Brink

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

M. Lia Palomba

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

Nihal Altan-Bonnet

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

Gregoire Altan-Bonnet

Memorial Sloan Kettering Cancer Center - ImmunoDynamics Group; Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

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Abstract

In cancer biology, 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, namely bimodality, hypersensitivity, and hysteresis, in the BCR signaling pathway of primary CLL B-cells. Such signaling abnormalities in CLL quantitatively derive from BCR clustering and constitutive signaling with positive feedback reinforcement, as demonstrated through single-cell analysis of signaling motifs, computational modeling, and super-resolution imaging. Such dysregulated signaling segregates CLL patients by disease severity and clinical presentation. These findings provide a novel quantitative framework and methodology to assess complex and heterogeneous leukemia pathology and to inform therapeutic strategies in parallel to genomic profiling.

Suggested Citation

Ziegler, Carly G. K. and Kim, Joel and Piersanti, Kelly and Oyler-Yaniv, Alon and Argyropoulos, Kimon V. and Brink, Marcel van den and Palomba, M. Lia and Altan-Bonnet, Nihal and Altan-Bonnet, Gregoire, Constitutive Activation of BCR Explains Dysfunctional Signaling in Chronic Lymphocytic Leukemia (March 5, 2019). Available at SSRN: https://ssrn.com/abstract=3346981 or http://dx.doi.org/10.2139/ssrn.3346981
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Carly G. K. Ziegler

Memorial Sloan Kettering Cancer Center - ImmunoDynamics Group

New York, NY 10065
United States

Joel Kim

Memorial Sloan Kettering Cancer Center - ImmunoDynamics Group

New York, NY 10065
United States

Kelly Piersanti

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

New York, NY 10065
United States

Alon Oyler-Yaniv

Memorial Sloan Kettering Cancer Center - ImmunoDynamics Group

New York, NY 10065
United States

Kimon V. Argyropoulos

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

New York, NY 10065
United States

Marcel van den Brink

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

New York, NY 10065
United States

M. Lia Palomba

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology

New York, NY 10065
United States

Nihal Altan-Bonnet

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

73 Mr. Wayte Avenue
Bethesda, MD 01702
United States

Gregoire Altan-Bonnet (Contact Author)

Memorial Sloan Kettering Cancer Center - ImmunoDynamics Group ( email )

New York, NY 10065
United States

Memorial Sloan Kettering Cancer Center - Center for Cancer Systems Biology ( email )

New York, NY 10065
United States

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