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Haematologica. 2019 May 16. pii: haematol.2018.215566. doi: 10.3324/haematol.2018.215566. [Epub ahead of print]

Responsiveness of Chronic Lymphocytic Leukemia cells to B cell receptor stimulation is associated with low expression of regulatory molecules of the Nuclear Factor-κB pathway.

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Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
Dept. of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;


Chronic lymphocytic leukemia is a heterogeneous disease based on clinical and biological characteristics. Differences in Ca2+-levels among cases, both basal and upon B-cell receptor stimulation may reflect heterogeneity in the pathogenesis due to cell-intrinsic factors. Our aim is to elucidate cell-intrinsic differences between B-cell receptor responsive and unresponsive cases. Therefore the B-cell receptor responsiveness was determined ex vivo based on Ca2+-influx upon α-IgM stimulation of purified chronic lymphocytic leukemia cell fractions of 52 patients. Phosphorylation levels of various B-cell receptor signaling molecules, and expression of activation markers were assessed by flow cytometry. Transcription profiling of responsive (n=6) and unresponsive cases (n=6) was performed by RNA sequencing. RQ-PCR was used to validate transcript level differences in a larger cohort. In 24 cases an α-IgM response was visible by Ca2+-influx which was accompanied by higher phosphorylation of PLCγ2 and Akt after α-IgM stimulation in combination with a higher surface expression of IgM, IgD, CD19, CD38 and CD43 compared to the unresponsive cases (n=28). Based on RNA sequencing analysis several components of the canonical NF-κB pathway especially related to NF-κB inhibition were higher expressed in unresponsive cases. Moreover, upon α-IgM stimulation, the expression of these NF-κB pathway genes (especially genes coding for NF-κB pathway inhibitors but also NF-κB subunit REL) are upregulated in B-cell receptor responsive cases while for the unresponsive cases the level did not change compared to basal levels. These findings suggest cells from chronic lymphocytic leukemia cases with an enhanced NF-κB signaling are associated with a lower responsive capacity towards B-cell receptor stimulation.


BCR responsiveness; Chronic Lymphocytic Leukemia; Cytogenetics and Molecular Genetics; Lymphocytes; NF-kB signaling

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