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B-cell signalling

Intracellular pathways and B-cell malignancies

In B-cell malignancies, the tumour microenvironment comprises stromal cells, T cells, soluble factors, and other cells in the lymphoid tissues that continuously influence B-cell development and growth.1,2 Interactions between this microenvironment and malignant B cells, which may resemble those with normal B cells, play an important role in B-cell homing, adhesion, and migration through activation of intracellular pathways in the B cells.1,3

 

When the B-cell receptor (BCR) and other signalling pathways become disrupted as a result of genetic mutations, they can promote the progression of B-cell malignancies.3–5

 

  • BCR=B-cell receptor.
  • NFκB=nuclear factor kappa-light-chain-
  • BTK=Bruton’s tyrosine kinase.
  • enhancer of activated B cells.
  • CXCR4/5=C–X–C (motif) chemokine receptor 4,
  • PKCβ=protein kinase C beta.
  • C–X–C (motif) chemokine receptor 5.
  • PLCγ2=phospholipase C gamma 2.
  • DAG=diacylglycerol.
  • PIP3=phosphatidylinositol-3,4,5-triphosphate.
  • FDC=follicular dendritic cell.
  • PI3K=phosphatidylinositide 3-kinases.
  • IP3=inositol triphosphate.
  • TLR=toll-like receptor.
  • MSC=mesenchymal stromal cell.
Creative representation of select simplified signaling pathways.2,3,6–8
* Based on in vitro data.

Prosurvival signals

Normal B cells rely on a complex network of prosurvival pathways initiated by the B cell receptor (BCR) to avoid apoptosis.9–11

 

In B-cell malignancies, interactions between malignant B cells and the tumour microenvironment may activate some of these pathways.1,9 This initiates signalling cascades dependent on several kinases, driving the uncontrolled survival and growth of malignant B cells.2

  • BCR=B-cell receptor.
  • BTK=Bruton’s tyrosine kinase.
  • NFκB=nuclear factor kappa-light-chain-enhancer of activated B cells.
  • PLCγ2=phospholipase C gamma 2.
Creative representation of select simplified signalling pathways.2,3,6
* Based on in vitro data.

B-cell homing

Cells circulating in the microenvironment secrete chemoattractant molecules to promote the homing of B cells to lymphoid tissues.1,12,13 These molecules exert their effects via signaling pathways involving several different kinases.1,3

 

In B-cell malignancies, B cells often express surface molecules which may promote homing to proliferative environments.1,6,14

Creative representation of select simplified signaling pathways.1,12,13
* Based on in vitro data.
Homing of B cells to the lymphoid tissues is promoted in B-cell malignancies1,12,13

Adhesion and migration

Adhesion molecules expressed by cells in the lymphoid tissue microenvironment bind to adhesion molecules on the surface of B cells to allow them to migrate through lymphoid tissues.1,14 These adhesion molecules also help to retain B cells within the lymphoid microenvironment, where the B cells can proliferate.1,14–16

 

In B-cell malignancies, the expression of certain adhesion molecules is dysregulated.14,16 The upregulation and increased migration of B cells may lead to further retention of B cells in proliferative environments and the promotion of chemoresistance.14,16,17

  • MSC=mesenchymal stromal cell.
  • VCAM-1=vascular cell adhesion molecule-1.
  • VLA-4=very late antigen-4.
Creative representation of select simplified signaling pathways.14,16,17
* Based on in vitro data.
Upregulation of adhesion molecules can lead to increased retention of B cells in proliferative
environments14,16,17
B-cell malignancies

B-cell malignancies include most non-Hodgkin lymphomas (NHL), some leukaemias, and myelomas.18

B-cell signalling

Insights into key pathways have helped identify new targets for treating B-cell malignancies.1,4,6,19

Resources

Click here to access our resources section, which contains a range of useful documents and links with more information about B-cell malignancies.

B-cell signalling

Click below to download the B-cell malignancies brochure.

/sites/default/files/DA Brochure.pdf

References

  1. Burger JA et al. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114(16):3367-3375.
  2. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120(24):4684-4691.
  3. de Gorter DJJ et al. Bruton’s tyrosine kinase and phospholipase Cγ2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26(1):93-104.
  4. Kil LP et al. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3(1):71-83. 
  5. Pighi C  et al. Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling. Cell Oncol (Dordr). 2011;34(1):141-153.
  6. Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol. 2012;31(2):119-132.
  7. Liu X et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat Immunol. 2011;12(5):416-424.
  8. Treon SP, Hunter ZR. A new era for Waldenstrom macroglobulinemia: MYD88 L265P. Blood. 2013;121(22):4434-4436.
  9. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175-1184.
  10. Rauch M et al. Crucial role for BAFF-BAFF-R signaling in the survival and maintenance of mature B cells. PLoS One. 2009;4(5):e5456.
  11. Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals. Immunol Cell Biol. 2007;85(6):471-475
  12. Okada T et al. Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J Exp Med. 2002;196(1):65-75.
  13. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:96-103.
  14. Kurtova AV et al. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009;113(19):4604-4613.
  15. Carrasco YR, Batista FD. B-cell activation by membranebound antigens is facilitated by the interaction of VLA-4 with VCAM-1. EMBO J. 2006;25(4):889-899.
  16. Binsky I et al. TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner. J Immunol. 2010;184(9):4761-4769.
  17. Kurtova AV et al Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood. 2009;114(20):4441-4450.
  18. Mitchell M et al. A multisource approach to improving epidemiologic estimates: application to global B-cell malignancies. ISRN Oncol. 2012; 2012:129713.
  19. ten Hacken, Burger J. Molecular pathways: targeting the microenvironment in chronic lymphocytic leukemia - focus on the B cell receptor. Clin Cancer Res. 2014;20(3):548-556