iwCLL 2017 | Additional signaling pathways in CLL and their interactions with the BCR

On 14^th May 2017, the “Role of the B-Cell Receptor and Other Signaling Pathways in CLL” took place at iwCLL, and was co-chaired by Nicholas Chiorazzi (The Feinstein Institute for Medical Research, Manhasset, NY, USA) and Kostas Stamatopoulos (Center for Research and Technology Hellas, Thessaloniki, Greece).

During this session, “Additional Signaling Pathways in CLL and Their Interactions With the BCR” was presented by Dimitar Efremov from the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.

The presentation began by outlining the evidence for a role of BCR signaling in the development and evolution of CLL (Iacovelli et al. 2015; Herishanu et al. 2011):

• Selection of stereotyped BCRs
• Correlation of clinical course with BCR-related features
• Clinical activity of BCR signaling inhibitors
• Selection of cell-autonomous BCRs and BCRs reactive with low-affinity autoantigens during leukemia development in Eµ transgenic mice
• Genes are differentially expressed:
  • Between lymph node and blood CLL cells
  • In CLL cells after in vitro BCR stimulation
  • BCR-regulated genes are enriched in lymph node CLL cells

CLL cells interact with T-cells and macrophages in proliferating centers in lymph nodes. Moreover, the interaction between activated T-cells and lymph node CLL cells has been reported in vivo and results in enrichment of IL-21 and IL-4 target genes in lymph node CLL cells.

BCR regulates proliferation of CLL cells via numerous mechanisms:

• Internalization of antigen and DNA-containing immune complexes: T-cell and TLR9 activation
• Inside-out integrin activation: tissue adhesion and retention (Buchner et al. 2010)

Dimitar Efremov asked is BCR signals are required for CLL proliferation? In patients and Eµ-TCL1 transgenic mice, BTK and SYK inhibitors rapidly inhibit proliferation of CLL cells. Moreover, stimulation of surface IgM induces expression of positive cell cycle regulators (MYC, CCND2) in a subset of CLL samples (Krysov et al. 2012). In patients and mouse models, BCR responsiveness positively correlates with disease severity and, in Eµ-TCL1 transgenic mice, enhanced BCR signaling correlates with enhanced proliferation of CLL cells.

There are a number of potential mechanisms to explain reduced surface IgM expression and BCR signaling capacity of CLL cells in the peripheral blood (Mockridge et al. 2007; Dühren-von Minden et al. 2012):

• Interactions with external autoantigens
• Cell-autonomous BCR-BCR interactions
• Interactions with soluble or FCµR-bound serum IgM

It has been found that serum IgM inhibits BCR signaling and that FCµR triggering alone is also sufficient to inhibit BCR signaling.

Additionally, IL-4 has been reported to upregulate expression of surface IgM and downregulates expression of FCµR on CLL cells. Also, FCµR expression is lower on lymph node CLL cells vs. peripheral blood CLL cells.

Moreover, serum IgM levels correlate with Treatment-Free Survival in U-CLL and inhibits expansion of human CLL cells xenografted in immunodeficient NSG mice.

Low FCµR levels are associated with a short Treatment-Free Survival and accelerates leukemia development in Eµ-TCL1 transgenic mice.

Dimitar Efremov concluded the talk with a concise summary slide: