B cell activation through CD40 and IL4R ligation modulates the response of chronic lymphocytic leukaemia cells to BAFF and APRIL.
The two tumour necrosis factor family proteins BAFF (TNFSF13B) and APRIL (TNFSF13) and their receptors [BAFF-R (TNFRSF13C), TACI (TNFRSF13B), BCMA (TNFRSF17)] play a critical role in the survival of normal B cells. The sensitivity of normal B cells to BAFF and APRIL can be modulated by signals regulated by their receptors. This modulation, however, has not been extensively investigated in chronic lymphocytic leukaemia (CLL) cells. We evaluated the expression, regulation and signalling of BAFF and APRIL receptors in normal and in CLL cells upon stimulation through CD40+IL4R and BCR. We further analysed the prognostic value of BAFF and APRIL receptors expression in patients with CLL. BCMA expression was significantly higher on CLL cells than on normal B cells. BCR and CD40+IL4R stimulation promoted an increase in TACI and BCMA expression, cell viability and activation in normal B cells. A similar effect was observed in CLL cells after CD40+IL4R but not BCR stimulation. BCMA expression correlated with unmutated IGHV genes, poor-risk cytogenetics, and short progression-free survival. These findings further characterize the link between CD40+IL4R regulatory signals, BAFF, APRIL and their receptors and the survival of leukaemic cells and clinical features of CLL.
Department of Haematology, Institute of Haematology and Oncology, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Gerardo
G
Ferrer
Rosa
R
Bosch
Kate
K
Hodgson
Rut
R
Tejero
Gael
G
Roué
Dolors
D
Colomer
Emili
E
Montserrat
Carol
C
Moreno
D053264:B-Cell Activating Factor / Q000276:immunology*; D053265:B-Cell Activation Factor Receptor / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000627:therapeutic use*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011947:Receptors, Antigen, B-Cell / Q000627:therapeutic use*; D015398:Signal Transduction; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D019013:CD40 Antigens; C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; D011947:Receptors, Antigen, B-Cell; C435926:TNFRSF13C protein, human; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha
B-cell maturation antigen; B-cell-activating factor; a proliferation-inducing ligand; chronic lymphocytic leukaemia; receptors modulation