Signaling Pathways Activated by the B-Cell Receptor in Chronic Lymphocytic Leukemia

Maria Teresa Scupoli; Giovanni Pizzolo


Expert Rev Hematol. 2012;5(3):341-348. 

In This Article

Role of Antigen Encounter

Although the nature of antigen and the mechanisms of BCR stimulation in vivo remain largely obscure, evidence suggests that antigen encounter is a crucial event for the onset and progression of B-CLL. Gene expression profiling studies provided the first evidence that B-CLL cells have a phenotype consistent with antigen-experienced, activated B cells.[61] More recent studies have revealed that the BCR signaling pathway signature is upregulated in LN compared with peripheral blood leukemic cells, thus identifying LN as a central site in B-CLL pathogenesis and, within the LN microenvironment, the BCR pathway as the most prominent pathogenetic mechanism in B-CLL.[30] In line with these findings, the LNs of patients with B-CLL are infiltrated with scattered microanatomical structures, known as proliferation centers or pseudofollicles, where B-CLL cells interact with bystander cells (i.e., stromal cells and T cells) and antigens, thus receiving survival and growth signals.[6] These microenvironmental signals complement intrinsic oncogenic lesions thus conferring growth advantage to the malignant clone.[6,30,62] Additional evidence of the importance of antigen in B-CLL comes from the finding that CLL B cells express a restricted IGHV gene repertoire and that expression of IGHV genes in B-CLL is not stochastic.[63–66] Furthermore, CLL B cells that express certain IGHV genes show a preferential use of the complementarity-determining region 3 (CDR3).[63,64] The CDR3 is the most variable region of the Ig heavy chain directly implicated in binding to conventional antigens; therefore, the expression of conserved Ig with restricted CDR3 is indicative that the Ig repertoire in B-CLL cells is highly selected, suggesting that they bind a limited set of antigens relevant to the pathogenesis of B-CLL. Furthermore, the finding that anergized IgM-mediated responses can recover signal capacity in vitro suggest the engagement of putative antigen in vivo.[67] Finally, the correlation with prognosis of several features of the BCR complex (i.e., the number of somatic mutations in the BCR and the expression of ZAP-70) suggests that B-cell selection and BCR stimulation have important roles in disease progression.[2,4,5]

The nature of promoting antigens is still unknown. However, B-CLL cells frequently have polyreactive BCRs, which bind multiple antigens, possible suggesting stimulation by both autoantigens and microbial antigens.[66]


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