The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy

Abstract

Biologists and clinicians agree that the B-cell receptor influences the behavior of chronic lymphocytic leukemia, and promising new drugs are aimed at receptor-associated kinases. Engagement of surface immunoglobulin by antigen is a key driver of malignant cells with outcome influenced by the nature of the cell, the level of stimulation and the microenvironment. Analysis of surface immunoglobulin-mediated signaling in the two major disease subsets defined by IGHV mutational status reveals bifurcation of responses toward proliferation or anergy. Mutated chronic lymphocytic leukemia, generally of relatively good prognosis, is mainly, but not exclusively, driven towards anergy in vivo. In contrast, unmutated chronic lymphocytic leukemia shows less evidence for anergy in vivo retaining more responsiveness to surface immunoglobulin M-mediated signaling, possibly explaining increased tumor progression. Expression and function of surface immunoglobulin M in unmutated chronic lymphocytic leukemia appear rather homogeneous, but mutated chronic lymphocytic leukemia exhibits a highly heterogeneous profile that may relate to further variable clinical behavior within this subset. Anergy should increase susceptibility to apoptosis but, in leukemic cells, this may be countered by overexpression of the B-cell lymphoma-2 survival protein. Maintained anergy spreads to chemokines and adhesion molecules, restraining homing and migration. However, anergy is not necessarily completely benign, being able to reverse and regenerate surface immunoglobulin M-mediated responses. A two-pronged attack on proliferative and anti-apoptotic pathways may succeed. Increased understanding of how chronic lymphocytic leukemia cells are driven to anergy or proliferation should reveal predictive biomarkers of progression and of likely response to kinase inhibitors, which could assist therapeutic decisions. ABSTRACT

Rewiring of sIgM-Mediated Intracellular Signaling through the CD180 Toll-like Receptor

“…However, in our hands, M-CLL samples were evenly distributed between AKT-S, p38MAPK-S and NS categories. Interestingly, all six DS CLL samples belonged to M-CLL group, which is associated with increased anergy (38). There were no phenotypic differences between the four signaling groups, apart from sIgD, that was highly expressed by p38MAPK-S compared with AKT-S cells: 83.5% ± 15.1% versus 48.5% ± 33.0%, p = 0.0055, n = 10.…”

“…Of note, CD180 nonsignaler CLL samples remained unresponsive to the ligation of sIgM that could indicate their anergic status (38).…”

Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

“…BCR-mediated signaling is deregulated in anergic B cells and these cells also exhibit an elevated basal [Ca 2+ ] I, by approximately 50-120 nM, but no further increase in [Ca 2+ ] i upon BCR stimulation (Cooke et al, 1994, Healy et al, 1997, Benschop et al, 2001, Yarkoni et al, 2010, Packham et al, 2014 (Healy et al, 1997 ) . In these HEL-anergic B-cells, BCR engagement induces low Ca 2+ oscillations and activates NF-AT and ERK, but does not activate NF-KB or JNK.…”

“…Anergy is one of the mechanisms adopted by the immune system to silence auto-reactive B cells upon low-affinity recognition of self Ag subsequent to BCR desensitization induced by chronic Ag binding (Gauld et al, 2006, Cambier et al, 2007, Muzio et al, 2008, Kurosaki et al, 2010, Packham et al, 2014. BCR-mediated signaling is deregulated in anergic B cells and these cells also exhibit an elevated basal [Ca 2+ ] I, by approximately 50-120 nM, but no further increase in [Ca 2+ ] i upon BCR stimulation (Cooke et al, 1994, Healy et al, 1997, Benschop et al, 2001, Yarkoni et al, 2010, Packham et al, 2014 (Healy et al, 1997 ) .…”

“…In these cells, BCR stimulation leads to a robust [Ca 2+ ] i increase, whereas B cells are unresponsive to such BCR cross-linking stimulation in the remaining cases. B cells from BCR non-responding CLL patients display constitutively phosphorylated extracellular signal-regulated kinase (ERK)1/2, constitutive phosphorylation of MEK1/2 (Mitogen activated Kinase Kinase 1/2) and an increase in nuclear factor of activated T cells (NF-AT) NF-AT2/NF-ATc1 translocation to the nucleus associated to a greater resistance to spontaneous apoptosis similar to anergic B cells (Petlickovski et al, 2005, Kurosaki et al, 2010, Packham et al, 2014.…”