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

Corso, Jasmin; Pan, Kuan-Ting; Walter, Roland B.; Doebele, Carmen; Mohr, Sebastian; Bohnenberger, Hanibal; Ströbel, Philipp; Lenz, Christof; Słabicki, Mikołaj; Hüllein, Jennifer; Comoglio, Federico; Rieger, Michael A.; Zenz, Thorsten; Wienands, Jürgen; Engelke, Michael; Serve, Hubert; Urlaub, Henning; Oellerich, Thomas

doi:10.1073/pnas.1601053113

Cited by 47 publications

(77 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1,3,4 A recent study systematically compared the biochemical nature of tonic and activated BCR signaling using a quantitative phosphoproteomic approach. 5 This work identified BCR-dependent phosphorylation events and distinct effectors for activated and tonic BCR signaling, implying a certain degree of specificity for these 2 BCR signaling modes. 5 Activated and tonic BCR signaling exhibit distinct vulnerabilities within the cell-intrinsic BCR signaling networks.…”

Section: Introductionmentioning

confidence: 81%

“…5 This work identified BCR-dependent phosphorylation events and distinct effectors for activated and tonic BCR signaling, implying a certain degree of specificity for these 2 BCR signaling modes. 5 Activated and tonic BCR signaling exhibit distinct vulnerabilities within the cell-intrinsic BCR signaling networks. In ABC-DLBCL, for example, mutated BCR signaling effectors lead to constitutively active BCR signaling and induce cell survival by activating NF-kB.…”

Section: Introductionmentioning

confidence: 81%

“…Moreover, 45% (85/187) of the identified downregulated pY sites have been previously identified as being involved in tonic BCR signaling. 5 This result suggests that HSP90 inhibition interferes with tonic antigenindependent BCR signaling. Consistently, a quantitative proteome analysis revealed downregulation of several BCR-proximal kinases including SYK, Src family tyrosine-protein kinase Lyn (LYN), and Bruton's tyrosine kinase (BTK) upon HSP90 inhibition ( Figure 2C).…”

Section: Hsp90 Inhibition Disrupts Tonic and Activated Bcr Signalingmentioning

confidence: 95%

“…After pY enrichment, peptides were desalted by using a self-made C18 stage-tip 14 and then dried in a SpeedVac. For each sample, 2 technical replicates were analyzed by mass spectrometry (MS) as described in Corso et al 5 Protein expression profiling was performed as described previously. 5 Liquid chromatography tandem MS analysis was performed on a Q Exactive HF (Thermo Fisher Scientific) mass spectrometer coupled with Ultimate 3000 RSLCnano System (Dionex).…”

Section: Ms and Protein Expression Analysismentioning

confidence: 99%

“…For each sample, 2 technical replicates were analyzed by mass spectrometry (MS) as described in Corso et al 5 Protein expression profiling was performed as described previously. 5 Liquid chromatography tandem MS analysis was performed on a Q Exactive HF (Thermo Fisher Scientific) mass spectrometer coupled with Ultimate 3000 RSLCnano System (Dionex). Phosphopeptides were first trapped on a homemade precolumn (ReproSil-Pur 120 C18-AQ, 5 mm; Dr. Maisch GmbH; 100 mm 3 5 cm) at 10 mL/minute of loading buffer (2% acetonitrile, 0.02% trifluoroacetic acid in water) and then separated on an analytical column (ReproSil-Pur 120 C18-AQ, 1.9 mm; Dr. Maisch GmbH, 75 mm 3 30 cm, selfpacked) with a 90-minute linear gradient ramping from 1% to 35% of buffer B (80% acetonitrile, 0.1% formic acid) followed by another 10-minute linear gradient to 60% buffer B with corresponding composition of buffer A (0.1% formic acid in water) at a constant flow rate of 300 nl/minute.…”

Section: Ms and Protein Expression Analysismentioning

confidence: 99%

See 4 more Smart Citations

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling

Walter

Pan

Doebele

et al. 2017

Blood

Self Cite

View full text Add to dashboard Cite

Key Points• HSP90 inhibition induces apoptosis in BL cells by disrupting tonic BCR signaling.• SYK is an HSP90 client protein, and BCR signalingdependent phosphorylation of HSP90 on Y197 is required for this interaction.Burkitt lymphoma (BL) is an aggressive B-cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Because of their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells. By global proteomic and phosphoproteomic profiling, we show that, in BL, HSP90 inhibition compromises the activity of the pivotal B-cell antigen receptor (BCR)-proximal effector spleen tyrosine kinase (SYK), which we identified as an HSP90 client protein. Consistently, expression of constitutively active TEL-SYK counteracted the apoptotic effect of HSP90 inhibition. Together, our results demonstrate that HSP90 inhibition impairs BL cell survival by interfering with tonic BCR signaling, thus providing a molecular rationale for the use of HSP90 inhibitors in the treatment of BL. (Blood. 2017;129(5):598-608)

show abstract

Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 81%

Section: Hsp90 Inhibition Disrupts Tonic and Activated Bcr Signalingmentioning

confidence: 95%

Section: Ms and Protein Expression Analysismentioning

confidence: 99%

Section: Ms and Protein Expression Analysismentioning

confidence: 99%

See 3 more Smart Citations

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling

Walter

Pan

Doebele

et al. 2017

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

Actinin‐4 controls survival signaling in B cells by limiting the lateral mobility of B‐cell antigen receptors

Alsouri,

Ambrose,

Mougios

et al. 2024

Eur J Immunol

Self Cite

View full text Add to dashboard Cite

The structure and dynamics of F‐actin networks in the cortical area of B cells control the signal efficiency of B‐cell antigen receptors (BCRs). Although antigen‐induced signaling has been studied extensively, the role of cortical F‐actin in antigen‐independent tonic BCR signaling is less well understood. Because these signals are essential for the survival of B cells and are consequently exploited by several B‐cell lymphomas, we assessed how the cortical F‐actin structure influences tonic BCR signal transduction. We employed genetic variants of a primary cell‐like B‐cell line that can be rendered quiescent to show that cross‐linking of actin filaments by α‐actinin‐4 (ACTN4), but not ACTN1, is required to preserve the dense architecture of F‐actin in the cortical area of B cells. The reduced cortical F‐actin density in the absence of ACTN4 resulted in increased lateral BCR diffusion. Surprisingly, this was associated with reduced tonic activation of BCR‐proximal effector proteins, extracellular signal‐regulated kinase, and pro‐survival pathways. Accordingly, ACTN4‐deficient B‐cell lines and primary human B cells exhibit augmented apoptosis. Hence, our findings reveal that cortical F‐actin architecture regulates antigen‐independent tonic BCR survival signals in human B cells.

show abstract

B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens

Bock

Bewarder

Cetin

et al. 2022

eJHaem

View full text Add to dashboard Cite

Burkitt lymphoma (BL) represents the most aggressive B-cell-lymphoma. Beside the hallmark of IG-MYC-translocation, surface B-cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra-nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum, a custom-made virome array and against self-antigens, including post-translationally modified antigens.An atypically modified, SUMOylated isoform of Bystin, that is, SUMO1-BYSL was identified as the antigen of the BCR of cell line CA46. SUMO1-BYSL was exclusively expressed in CA46 cells with K139 as site of the SUMOylation. Secondly, an

show abstract

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

Cited by 47 publications

References 50 publications

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling

Actinin‐4 controls survival signaling in B cells by limiting the lateral mobility of B‐cell antigen receptors

B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens

Contact Info

Product

Resources

About