The International Journal of Developmental Biology

Int. J. Dev. Biol. 59: 379 - 389 (2015)

Vol 59, Issue 7-8-9

Special Issue: Ionic Messengers in Development and Cancer

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

Published: 19 November 2015

Marjolaine Debant1,2,3, Patrice Hemon1,2,3, Christophe Brigaudeau1,3 , Yves Renaudineau2,3 and Olivier Mignen*,1,3

1INSERM U1078, Brest University Medical School, Brest, 2INSERM ESPRI, ERI29/EA2216 Laboratory of Immunotherapy and B Cell Pathologies, CHRU Morvan, European University of Brittany, Brest and 3 Network “Ion channels and cancer-Cancéropole Grand Ouest, (IC-CGO), France


Ca2+ signaling is a key regulator of B lymphocyte cell fate and defects in this signaling pathway have been reported in numerous diseases such as Chronic lymphocytic leukemia (CLL). CLL is a B cell clonal disorder characterized by the accumulation of mature monoclonal CD5+ B cells. Although CLL could be considered to be a proliferative disease, most circulating CLL B cells are arrested in the G0 phase of the cell cycle and present both defects in calcium (Ca2+) homeostasis and signaling. The Ca2+ response to antigen ligation is heterogeneous and related, in part, to defects arising from the incapacity to respond to B cell receptor (BCR) engagement (anergy), to the expression of T cell kinases (e.g. Zap70), and to the presence of negative feedback regulation by phosphatases (e.g. SHP-1). Anergic CD5+ CLL B cells are characterized by an elevated basal Ca2+ level, IgM/CD79 downregulation, a constitutive activation of BCR pathway kinases, and an activation of the nuclear factor of activated T cells (NF-AT). Based on the Ca2+ response, patients are classified into three groups: unresponders, responders with apoptosis, and responders with entry in the cell cycle. Moreover, internal and direct interaction between leukemic BCR-HCDR3 epitopes at the plasma membrane and interaction between Bcl-2 and the IP3-receptor at the endoplasmic reticulum are also suspected to interfere with the intracellular Ca2+ homeostasis in CLL-B cells. As a whole, the Ca2+ pathway is emerging to play a key role in malignant CLL-B survival, disease progression, and last but not least, in the therapeutic response.


calcium, chronic lymphocytic leukaemia, CD5, cell fate

Full text in web format is not available for this article. Please download the PDF version.