Dataset Information

Elucidation of tonic and activated B cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

ABSTRACT: B-cell receptor (BCR) signaling promotes the survival of malignant B cells, such as Burkitt’s lymphoma (BL) and the activated B-cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL). In contrast to ABC DLBCL, where malignant cells require chronic activation of the BCR for their survival, BL cells are dependent on tonic BCR signaling that is antigen-independent. Elucidation and systematic comparison of tonic and activated BCR signaling led to the identification of novel signaling effectors, among them ACTN4 and ARFGEF2, which were identified as regulators of BL cell survival. As tonic and activated BCR signaling are relevant for important aspects of B cell biology, our study helps in gaining an understanding of BCR-induced processes not only in malignant but potentially also physiological settings.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Suspension Culture

DISEASE(S): Lymphoma

SUBMITTER: Kuan-Ting Pan

LAB HEAD: Henning Urlaub

PROVIDER: PXD003492 | Pride | 2016-05-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	DG75_BCRstim_GP_A1_F10_1.raw	Raw
	DG75_BCRstim_GP_A1_F10_2.raw	Raw
	DG75_BCRstim_GP_A1_F11_1.raw	Raw
	DG75_BCRstim_GP_A1_F11_2.raw	Raw
	DG75_BCRstim_GP_A1_F12_1.raw	Raw

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Elucidation of tonic and activated B-cell receptor signaling in Burkitt's lymphoma provides insights into regulation of cell survival.

Corso Jasmin J Pan Kuan-Ting KT Walter Roland R Doebele Carmen C Mohr Sebastian S Bohnenberger Hanibal H Ströbel Philipp P Lenz Christof C Slabicki Mikolaj M Hüllein Jennifer J Comoglio Federico F Rieger Michael A MA Zenz Thorsten T Wienands Jürgen J Engelke Michael M Serve Hubert H Urlaub Henning H Oellerich Thomas T

Proceedings of the National Academy of Sciences of the United States of America 20160506 20

Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and ...[more]

PMID: 27155012

Similar Datasets

Project description:The B cell receptor (BCR) signaling, required for the survival and maturation of B cells, is a major deregulated pathway in B cell lymphomas. Several mutations are known to enhance the tonic BCR signal in Burkitt lymphomas (BL) or to mimic an activated receptor in some diffuse large B cell lymphomas (DLBCL). While the proximal events and kinases of the BCR signaling are well studied, less is known about the interactions of downstream effector pathways. In order to reach a less abstract description of this pathway we decided to employ the Modular Response Analysis-based modelling approach STASNet on more directly connected phosphorylation data. Using a Luminex proteomics platform we measured the phosphorylation of fourteen signaling and effector proteins after activating the B cell receptor (BCR) signaling and/or using inhibitors directed against seven intracellular signaling molecules in two independent Burkitt lymphoma cells (BL-2, BL-41). Application of a novel two step STASNet modelling pipeline unveiled novel feedback and crosstalk structures in the BCR-driven signaling network, including a crosstalk from p38 which negatively regulates MEK/ERK-activity in the presence of active BCR. Using Western Blot measurements, we verified and further characterized the p38-MEK/ERK crosstalk and demonstrated that it is a general mechanism in BL cells. Global Tandem Mass Tag (TMT) phosphoproteomic analysis on BL-2 cells found PI3K to be a major mediator of B-cell receptor signaling and manifested the p38-ERK crosstalk directly on ERK phosphosites and indirectly on seven bona fide ERK targets. We also noticed that the BL-2-learned pathway network structure was transferable to perturbation data from closely related BL-41 cells. Moreover, - compared to a literature-derived network - the BL-2-developed predictive pathway proved also to be a better starting point for network development in cells with aberrant BCR signaling in two representative cell lines derived from Diffuse large B cells (HBL-1, OCI-LY3). This indicates that models trained on activated B-cells are highly informative to be transferred to closely related cancer signaling network.