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

Ziegler, Carly G. K.; Kim, Joel; Piersanti, Kelly; Oyler-Yaniv, Alon; Argyropoulos, Kimon V.; Brink, Marcel R.M. van den; Palomba, M. Lia; Altan‐Bonnet, Nihal; Altan‐Bonnet, Grégoire

doi:10.1016/j.celrep.2019.06.069

Cited by 17 publications

(21 citation statements)

References 50 publications

(59 reference statements)

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“…Indeed, induction of stable BCR clustering on healthy B cells modulated BCR responsiveness. In fact, by titrating the amount of anti-IgM crosslinking, healthy B cells could be induced to recapitulate the diversity in signaling observed in CLL cells, confirming that BCR clustering can modulate BCR responsiveness and thereby phenocopy the signaling dysfunction in CLL ( 71 ). As for the heterogeneity of BCR responsiveness, CLL cells could be divided into 3 subgroups of SHP-1 low /pPLCG2 high to SHP-1 high /pPLCG2 low expression, where each subset displayed unique deviations in their BCR signaling responses ( 71 ).…”

Section: Evidence For Non-bcr Signals In Vivomentioning

confidence: 81%

“…In fact, by titrating the amount of anti-IgM crosslinking, healthy B cells could be induced to recapitulate the diversity in signaling observed in CLL cells, confirming that BCR clustering can modulate BCR responsiveness and thereby phenocopy the signaling dysfunction in CLL ( 71 ). As for the heterogeneity of BCR responsiveness, CLL cells could be divided into 3 subgroups of SHP-1 low /pPLCG2 high to SHP-1 high /pPLCG2 low expression, where each subset displayed unique deviations in their BCR signaling responses ( 71 ). As increasing levels of SHP-1 and decreasing levels of pPLCG2 correlated with weakened BCR responsiveness, this suggests that phenotypic variability within isogenic populations of cells may result from heterogeneous levels of signaling regulators ( 71 ).…”

Section: Evidence For Non-bcr Signals In Vivomentioning

confidence: 81%

“…This also suggests a mutual BCR recognition on CLL cells which was confirmed by the binding of secreted CLL-derived BCRs to the surface of cell lines expressing either CLL or HD BCRs, but not to cells that did not express a BCR ( 70 ). Likewise, serum immunoglobulins from HD plasma were not able to bind HD B cells whereas serum immunoglobulins from CLL plasma were ( 71 ). It was shown that the binding was mediated by a conserved epitope in the second framework region of VH domains of the CLL BCR, as point mutations inside this motif abolished autonomous signaling.…”

Section: In Vivo Cll Proliferationmentioning

confidence: 99%

“…Another possibility is that the variability in BCR responses stems from variable degrees of sIg clustering, which may be associated with natural genomic heterogeneity in BCRs and/or response to antigen ( 71 ). Indeed, induction of stable BCR clustering on healthy B cells modulated BCR responsiveness.…”

Section: Evidence For Non-bcr Signals In Vivomentioning

confidence: 99%

“…As for the heterogeneity of BCR responsiveness, CLL cells could be divided into 3 subgroups of SHP-1 low /pPLCG2 high to SHP-1 high /pPLCG2 low expression, where each subset displayed unique deviations in their BCR signaling responses ( 71 ). As increasing levels of SHP-1 and decreasing levels of pPLCG2 correlated with weakened BCR responsiveness, this suggests that phenotypic variability within isogenic populations of cells may result from heterogeneous levels of signaling regulators ( 71 ).…”

Section: Evidence For Non-bcr Signals In Vivomentioning

confidence: 99%

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Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing?

2020

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Chronic lymphocytic leukemia (CLL) cells cycle between lymphoid tissue sites where they actively proliferate, and the peripheral blood (PB) where they become quiescent. Strong evidence exists for a crucial role of B cell receptor (BCR) triggering, either by (self-)antigen or by receptor auto-engagement in the lymph node (LN) to drive CLL proliferation and provide adhesion. The clinical success of Bruton’s tyrosine kinase (BTK) inhibitors is widely accepted to be based on blockade of the BCR signal. Additional signals in the LN that support CLL survival derive from surrounding cells, such as CD40L-presenting T helper cells, myeloid and stromal cells. It is not quite clear if and to what extent these non-BCR signals contribute to proliferation in situ. In vitro BCR triggering, in contrast, leads to low-level activation and does not result in cell division. Various combinations of non-BCR signals delivered via co-stimulatory receptors, Toll-like receptors (TLRs), and/or soluble cytokines are applied, leading to comparatively modest and short-lived CLL proliferation in vitro . Thus, an unresolved gap exists between the condition in the patient as we now understand it and applicable knowledge that can be harnessed in the laboratory for future therapeutic applications. Even in this era of targeted drugs, CLL remains largely incurable with frequent relapses and emergence of resistance. Therefore, we require better insight into all aspects of CLL growth and potential rewiring of signaling pathways. We aim here to provide an overview of in vivo versus in vitro signals involved in CLL proliferation, point out areas of missing knowledge and suggest future directions for research.

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Section: Evidence For Non-bcr Signals In Vivomentioning

confidence: 81%

Section: Evidence For Non-bcr Signals In Vivomentioning

confidence: 81%

Section: In Vivo Cll Proliferationmentioning

confidence: 99%

Section: Evidence For Non-bcr Signals In Vivomentioning

confidence: 99%

Section: Evidence For Non-bcr Signals In Vivomentioning

confidence: 99%

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Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing?

2020

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Human TCR repertoire in cancer

Chen,

Hu,

Zheng

et al. 2024

Cancer Medicine

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BackgroundT cells, the “superstar” of the immune system, play a crucial role in antitumor immunity. T‐cell receptors (TCR) are crucial molecules that enable T cells to identify antigens and start immunological responses. The body has evolved a unique method for rearrangement, resulting in a vast diversity of TCR repertoires. A healthy TCR repertoire is essential for the particular identification of antigens by T cells.MethodsIn this article, we systematically summarized the TCR creation mechanisms and analysis methodologies, particularly focusing on the application of next‐generation sequencing (NGS) technology. We explore the TCR repertoire in health and cancer, and discuss the implications of TCR repertoire analysis in understanding carcinogenesis, cancer progression, and treatment.ResultsThe TCR repertoire analysis has enormous potential for monitoring the emergence and progression of malignancies, as well as assessing therapy response and prognosis. The application of NGS has dramatically accelerated our comprehension of TCR diversity and its role in cancer immunity.ConclusionsTo substantiate the significance of TCR repertoires as biomarkers, more thorough and exhaustive research should be conducted. The TCR repertoire analysis, enabled by advanced sequencing technologies, is poised to become a crucial tool in the future of cancer diagnosis, monitoring, and therapy evaluation.

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Modeling immune cell behavior across scales in cancer

Makaryan

Cess

Finley

2020

WIREs Mechanisms of Disease

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Detailed, mechanistic models of immune cell behavior across multiple scales in the context of cancer provide clinically relevant insights needed to understand existing immunotherapies and develop more optimal treatment strategies. We highlight mechanistic models of immune cells and their ability to become activated and promote tumor cell killing. These models capture various aspects of immune cells: (a) single‐cell behavior by predicting the dynamics of intracellular signaling networks in individual immune cells, (b) multicellular interactions between tumor and immune cells, and (c) multiscale dynamics across space and different levels of biological organization. Computational modeling is shown to provide detailed quantitative insight into immune cell behavior and immunotherapeutic strategies. However, there are gaps in the literature, and we suggest areas where additional modeling efforts should be focused to more prominently impact our understanding of the complexities of the immune system in the context of cancer. This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Models of Systems Properties and Processes > Cellular Models

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

Cited by 17 publications

References 50 publications

Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing?

Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing?

Human TCR repertoire in cancer

Modeling immune cell behavior across scales in cancer

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