TY - JOUR
T1 - Toll-like receptor signaling pathway in chronic lymphocytic leukemia
T2 - Distinct gene expression profiles of potential pathogenic significance in specific subsets of patients
AU - Arvaniti, Eleni
AU - Ntoufa, Stavroula
AU - Papakonstantinou, Nikos
AU - Touloumenidou, Tasoula
AU - Laoutaris, Nikolaos
AU - Anagnostopoulos, Achilles
AU - Lamnissou, Klea
AU - Caligaris-Cappio, Federico
AU - Stamatopoulos, Kostas
AU - Ghia, Paolo
AU - Muzio, Marta
AU - Belessi, Chrysoula
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Background Signaling through the B-cell receptor appears to be a major contributor to the pathogenesis of chronic lymphocytic leukemia. Toll-like receptors bridge the innate and adaptive immune responses by acting as co-stimulatory signals for B cells. The available data on the expression of Toll-like receptors in chronic lymphocytic leukemia are limited and derive from small series of patients. Design and Methods We profiled the expression of genes associated with Toll-like receptor signaling pathways in 192 cases of chronic lymphocytic leukemia and explored potential associations with molecular features of the clonotypic B-cell receptors. Results Chronic lymphocytic leukemia cells express all Toll-like receptors expressed by normal activated B cells, with high expression of TLR7 and CD180, intermediate expression of TLR1, TLR6, TLR10 and low expression of TLR2 and TLR9. The vast majority of adaptors, effectors and members of the NFKB, JNK/p38, NF/IL6 and IRF pathways are intermediately-to-highly expressed, while inhibitors of Toll-like receptor activity are generally low-to-undetectable, indicating that the Toll-like receptor-signaling framework is competent in chronic lymphocytic leukemia. Significant differences were identified for selected genes between cases carrying mutated or unmutated IGHV genes or assigned to different subsets with stereotyped B-cell receptors. The differentially expressed molecules include receptors, NFkB/MAPK signaling molecules and final targets of the cascade. Conclusions The observed variations are suggestive of distinctive activation patterns of the Toll-like receptor signaling pathway in subgroups of cases of chronic lymphocytic leukemia defined by the molecular features of B-cell receptors. Additionally, they indicate that different or concomitant signals acting through receptors other than the B-cell receptor can affect the behavior of the malignant clone.
AB - Background Signaling through the B-cell receptor appears to be a major contributor to the pathogenesis of chronic lymphocytic leukemia. Toll-like receptors bridge the innate and adaptive immune responses by acting as co-stimulatory signals for B cells. The available data on the expression of Toll-like receptors in chronic lymphocytic leukemia are limited and derive from small series of patients. Design and Methods We profiled the expression of genes associated with Toll-like receptor signaling pathways in 192 cases of chronic lymphocytic leukemia and explored potential associations with molecular features of the clonotypic B-cell receptors. Results Chronic lymphocytic leukemia cells express all Toll-like receptors expressed by normal activated B cells, with high expression of TLR7 and CD180, intermediate expression of TLR1, TLR6, TLR10 and low expression of TLR2 and TLR9. The vast majority of adaptors, effectors and members of the NFKB, JNK/p38, NF/IL6 and IRF pathways are intermediately-to-highly expressed, while inhibitors of Toll-like receptor activity are generally low-to-undetectable, indicating that the Toll-like receptor-signaling framework is competent in chronic lymphocytic leukemia. Significant differences were identified for selected genes between cases carrying mutated or unmutated IGHV genes or assigned to different subsets with stereotyped B-cell receptors. The differentially expressed molecules include receptors, NFkB/MAPK signaling molecules and final targets of the cascade. Conclusions The observed variations are suggestive of distinctive activation patterns of the Toll-like receptor signaling pathway in subgroups of cases of chronic lymphocytic leukemia defined by the molecular features of B-cell receptors. Additionally, they indicate that different or concomitant signals acting through receptors other than the B-cell receptor can affect the behavior of the malignant clone.
KW - Chronic lymphocytic leukemia
KW - Gene expression profiling
KW - Signaling pathway
KW - Toll-like receptor
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U2 - 10.3324/haematol.2011.044792
DO - 10.3324/haematol.2011.044792
M3 - Article
C2 - 21750087
AN - SCOPUS:80355126549
VL - 96
SP - 1644
EP - 1652
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 11
ER -