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

https://doi.org/10.1387/ijdb.150204om

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 Debant^1,2,3, Patrice Hemon^1,2,3, Christophe Brigaudeau^1,3 , Yves Renaudineau^2,3 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

Abstract

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.

Keywords

calcium, chronic lymphocytic leukaemia, CD5, cell fate