Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?
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Marjolaine Debant [2] ; Patrice Hemon [2] ; Christophe Brigaudeau [2] ; Yves Renaudineau [1] ; Olivier Mignen [2]
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[1] European University of Brittany
European University of Brittany
Arrondissement de Rennes, Francia
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[2] Brest University Medical School
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- Localización: International journal of developmental biology, ISSN 0214-6282, Vol. 59, Nº. Extra 7-9, 2015 (Ejemplar dedicado a: Ionic Messengers in Development and Cancer), págs. 379-389
- Idioma: inglés
- Texto completo no disponible (Saber más ...)
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Resumen
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.
