TY - JOUR
TI - Toll-like receptor signaling pathway in chronic lymphocytic leukemia: Distinct gene expression profiles of potential pathogenic significance in specific subsets of patients
AU - Arvaniti, E.
AU - Ntoufa, S.
AU - Papakonstantinou, N.
AU - Touloumenidou, T.
AU - Laoutaris, N.
AU - Anagnostopoulos, A.
AU - Lamnissou, K.
AU - Caligaris-Cappio, F.
AU - Stamatopoulos, K.
AU - Ghia, P.
AU - Muzio, M.
AU - Belessi, C.
JO - Haematologica-the hematology journal
PY - 2011
VL - 96
TODO - 11
SP - 1644-1652
PB - 
SN - null
TODO - 10.3324/haematol.2011.044792
TODO - B lymphocyte receptor;  CD180 antigen;  immunoglobulin enhancer binding protein;  interferon regulatory factor;  interleukin 6;  lymphocyte antigen;  mitogen activated protein kinase p38;  stress activated protein kinase;  toll like receptor;  toll like receptor 1;  toll like receptor 10;  toll like receptor 2;  toll like receptor 6;  toll like receptor 7;  toll like receptor 9;  unclassified drug, article;  B lymphocyte;  cancer survival;  CD180 gene;  chronic lymphatic leukemia;  controlled study;  gene;  gene expression profiling;  gene mutation;  human;  human cell;  IL6 gene;  immunoglobulin heavy chain gene;  IRF gene;  JNK gene;  major clinical study;  MAPK gene;  NF gene;  NFkB gene;  overall survival;  p38 gene;  progression free survival;  protein expression;  TLR1 gene;  TLR10 gene;  Tlr2 gene;  TLR6 gene;  TLR7 gene;  TLR9 gene, B-Lymphocytes;  Female;  Gene Expression Profiling;  Gene Expression Regulation, Leukemic;  Humans;  Leukemia, Lymphocytic, Chronic, B-Cell;  Male;  MAP Kinase Signaling System;  Neoplasm Proteins;  Oligonucleotide Array Sequence Analysis;  Toll-Like Receptors
TODO - 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. © 2011 Ferrata Storti Foundation.
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