title: Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients.
abstract: 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.
  
  
  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, NFκB/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.
authors.affiliation: School of Biology, University of Athens, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Arvaniti
authors.forename: Stavroula
authors.initials: S
authors.lastname: Ntoufa
authors.forename: Nikos
authors.initials: N
authors.lastname: Papakonstantinou
authors.forename: Tasoula
authors.initials: T
authors.lastname: Touloumenidou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Laoutaris
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.forename: Klea
authors.initials: K
authors.lastname: Lamnissou
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: Marta
authors.initials: M
authors.lastname: Muzio
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Belessi
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins; D051193:Toll-Like Receptors