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B-cell malignancies

Defining new directions in B-cell malignancies

B-cell malignancies represent a diverse collection of diseases, including most non-Hodgkin’s lymphomas (NHL), some leukaemias, and myelomas. Examples include chronic lymphocytic leukaemia, follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma.1

B-cell malignancies make up about 85% of all NHL worldwide.2,3

B-cell malignancies are divided into 2 broad clinical categories3–5

Indolent

Indolent malignancies, such as follicular lymphoma, small lymphocytic lymphoma and marginal zone lymphoma, are characterised by slow growth and a high initial response rate, followed by a relapsing and progressive disease course.4,5

 
  

Aggressive

Aggressive lymphomas, such as diffuse large B-cell lymphoma, mantle cell lymphoma and Burkitt’s lymphoma, are characterised by rapid growth and lower initial response rates, with shorter overall survival (OS).3-5

Development of B cells

B cells go through multiple stages of development in their lifecycles. There are many different identifiable stages of normal B cells and similarly many different types of B-cell malignancies. Each type of B-cell malignancy can be related to specific stages in the development of normal B cells.6-8

The variety of B-cell malignancies shown here are broadly mapped to normal B-cell differentiation stages, but the exact point at which B cells become malignant is not simple to define.6,7

Oncogenesis of B cells

Interactions between the 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.9,10

  • 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.10–16
* Based on in vitro data.
B-cell malignancies

B-cell malignancies include most non-Hodgkin lymphomas (NHL), some leukaemias, and myelomas.2

B-cell signalling

Insights into key pathways have helped identify new targets for treating B-cell malignancies.9,11,15,17

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. National Comprehensive Cancer Network. Non-Hodgkin’s Lymphomas, version 1. 2014.
  2. Mitchell M et al. A multisource approach to improving epidemiologic estimates: application to global B-cell malignancies. ISRN Oncol. 2012;2012:129713.
  3. Dotan E et al. Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin’s Lymphoma. P T. 2010;35(3):148-157.
  4. Guerard EJ, Bishop MR. Overview of non-Hodgkin’s lymphoma. Dis Mon. 2012;58(4):208-218.
  5. Vidal L et al. Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012 Sep 12;9:CD009045.
  6. Shaffer AL III, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol. 2012;30:565-610.
  7. Küppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5(4):251-262.
  8. Murphy K et al. Janeway's Immunobiology. 7th ed. New York, NY: Garland Science; 2008.
  9. Burger JA et al. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114(16):3367-3375.
  10. 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.
  11. Buggy JJ, Elias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol. 2012;31(2):119-132.
  12. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120(24):4684-4691.
  13. 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.
  14. Treon SP, Hunter ZR. A new era for Waldenstrom macroglobulinemia: MYD88 L265P. Blood. 2013;121(22):4434-4436.
  15. 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.
  16. 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.
  17. ten Hacken E, 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.