title: Calcium signaling and cell fate: how can Ca2+ signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?
abstract: Ca(2+) 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 (Ca(2+)) homeostasis and signaling. The Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) homeostasis in CLL-B cells. As a whole, the Ca(2+) pathway is emerging to play a key role in malignant CLL-B survival, disease progression, and last but not least, in the therapeutic response.
authors.affiliation: INSERM U1078, Brest University Medical School, Brest, France.
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Debant
authors.forename: Patrice
authors.initials: P
authors.lastname: Hemon
authors.forename: Christophe
authors.initials: C
authors.lastname: Brigaudeau
authors.forename: Yves
authors.initials: Y
authors.lastname: Renaudineau
authors.forename: Olivier
authors.initials: O
authors.lastname: Mignen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology
chemical_list: D002118:Calcium