Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors

Stavroula Ntoufa, Anna Vardi, Nikos Papakonstantinou, Achilles Anagnostopoulos, Vassiliki Aleporou-Marinou, Chrysoula Belessi, Paolo Ghia, Federico Caligaris-Cappio, Marta Muzio, Kostas Stamatopoulos

Research output: Contribution to journalArticle

Abstract

Subgroups of patients with chronic lymphocytic leukemia (CLL) have distinct expression profiles of Toll-like receptor (TLR) pathway-associated genes. To test the hypothesis that signaling through innate immunity receptors may influence the behavior of the malignant clone, we investigated the functional response triggered by the stimulation of TLRs and NOD2 in 67 CLL cases assigned to different subgroups on the basis of immunoglobulin heavy variable (IGHV) gene usage, IGHV gene mutational status or B-cell receptor (BcR) stereotypy. Differences in the induction of costimulatory molecules and/or apoptosis were observed in mutated versus unmutated CLL. Different responses were also identified in subsets with stereotyped BcRs, underscoring the idea that "subset-biased" innate immunity responses may occur independently of mutational status. Additionally, differential modulation of kinase activities was induced by TLR stimulation of different CLL subgroups, revealing a TLR7-tolerant state for cases belonging to stereotyped subset #4. The distinct patterns of TLR/NOD2 functional activity in cells from CLL subgroups defined by the molecular features of the clonotypic BcRs might prove relevant for elucidating the immune mechanisms underlying CLL natural history and for defining subgroups of patients who might benefit from treatment with specific TLR ligands.

Original languageEnglish
Pages (from-to)1281-1291
Number of pages11
JournalMolecular medicine (Cambridge, Mass.)
Volume18
Issue number9
DOIs
Publication statusPublished - 2012

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ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Ntoufa, S., Vardi, A., Papakonstantinou, N., Anagnostopoulos, A., Aleporou-Marinou, V., Belessi, C., Ghia, P., Caligaris-Cappio, F., Muzio, M., & Stamatopoulos, K. (2012). Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors. Molecular medicine (Cambridge, Mass.), 18(9), 1281-1291. https://doi.org/10.2119/molmed.2011.00480