Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients

Arvaniti, Eleni; Ntoufa, Stavroula; Papakonstantinou, Nikos; Touloumenidou, Tasoula; Laoutaris, Nikolaos; Anagnostopoulos, Achilles; Lamnissou, Klea; Caligaris-Cappio, Federico; Stamatopoulos, Kostas; Ghia, Paolo; Muzio, Marta; Belessi, Chrysoula

doi:10.3324/haematol.2011.044792

Cited by 78 publications

(82 citation statements)

References 50 publications

(52 reference statements)

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“…10,[15][16][17][18][19][20][21][22][23][24][25] In addition, preliminary observations in CLL, in relatively small patient series, suggest that the frequency and patterns of mutations within several genes, namely, NOTCH1, SF3B1 and TP53, may differ amongst subsets of patients carrying stereotyped BcRs, the paradigmatic example being the recently observed enrichment of SF3B1 mutations in the clinically aggressive subset #2. [26][27][28] With this in mind, we sought to systematically evaluate the mutational status of BIRC3, MYD88, NOTCH1, SF3B1 and TP53 in 565 CLL patients assigned to one of 10 major stereotyped subsets, and representing cases with varying SHM status, i.e.…”

Section: Different Spectra Of Recurrent Gene Mutations In Subsets Of mentioning

confidence: 99%

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

et al. 2016

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We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).

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Section: Different Spectra Of Recurrent Gene Mutations In Subsets Of mentioning

confidence: 99%

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

et al. 2016

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“…Recent studies by us (14,15) and others (16) have demonstrated that CLL patient subgroups defined by specific molecular characteristics of their clonotypic BcRs have distinct patterns of TLR pathway gene expression, function and/or tolerance. These findings indicate that specific modalities of BcR/TLR collaboration and/or regulation may eventually affect the biological behavior of the malignant clones.…”

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Differential microRNA Profiles and Their Functional Implications in Different Immunogenetic Subsets of Chronic Lymphocytic Leukemia

Papakonstantinou

Ntoufa

Chartomatsidou

et al. 2013

Mol Med

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Critical processes of B-cell physiology, including immune signaling through the B-cell receptor (BcR) and/or Toll-like receptors (TLRs), are targeted by microRNAs. With this in mind and also given the important role of BcR and TLR signaling and microRNAs in chronic lymphocytic leukemia (CLL), we investigated whether microRNAs could be implicated in shaping the behavior of CLL clones with distinct BcR and TLR molecular and functional profiles. To this end, we examined 79 CLL cases for the expression of 33 microRNAs, selected on the following criteria: (a) deregulated in CLL versus normal B-cells; (b) differentially expressed in CLL subgroups with distinct clinicobiological features; and, (c) if meeting (a) + (b), having predicted targets in the immune signaling pathways. Significant upregulation of miR-150, miR-29c, miR-143 and miR-223 and downregulation of miR-15a was found in mutated versus unmutated CLL, with miR-15a showing the highest fold difference. Comparison of two major subsets with distinct stereotyped BcRs and signaling signatures, namely subset 1 [IGHV1/5/7-IGKV1(D)-39, unmutated, bad prognosis] versus subset 4 [IGHV4-34/IGKV2-30, mutated, good prognosis] revealed differences in the expression of miR-150, miR-29b, miR-29c and miR-101, all down-regulated in subset 1. We were also able to link these distinct microRNA profiles with cellular phenotypes, importantly showing that, in subset 1, miR-101 downregulation is associated with overexpression of the enhancer of zeste homolog 2 (EZH2) protein, which has been associated with clinical aggressiveness in other B-cell lymphomas. In conclusion, specific miRNAs differentially expressed among CLL subgroups with distinct BcR and/or TLR signaling may modulate the biological and clinical behavior of the CLL clones.

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“…Data analysis was performed as previously reported. 21 We assigned a "High expression level" to mRNAs showing an average ΔCt≤6.6; "Intermediate expression level" to mRNAs showing an average ΔCt>6.6 and ≤9.9; "Low expression level" to mRNAs showing an average ΔCt>9.9 and ≤13.2 and "Negative expression" to mRNAs showing an average ΔCt>13.2. …”

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Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nadaptor molecule MyD88 connects distinct TLRs to proximal IRAK kinases which then trigger a cascade of phosphorylation events, eventually leading to MAPK and IKK activation and the induction of specific transcriptional programs including that of the NF-κB complex. 16 With all the above in mind, we herein aimed at characterizing TLR expression and function in SMZL, in order to assess the potential impact of TLR signaling on the biology of this disease. Methods Cell purificationBlood and tissue samples were obtained from SMZL patients after informed consent as part of a study (ViVi-NHL) approved by the institutional ethics committee. SMZL cells were negatively selected and purified using a B-cell enrichment kit (RosetteSep; StemCell Technologies) following the manufacturer's instructions. Normal B cells were purified by negative selection (EasySep; StemCell Technologies) from buffy coats. Preparations were virtually devoid of NK cells, T-lymphocytes and monocytes.In 19 SMZL cases, total peripheral blood mononuclear cells (PBMC) were isolated by Ficoll gradient centrifugation without further purification (the percentage of CD19 + cells in these cases is reported in Online Supplementary Table S1). In all cases, subsequent flow cytometric analyses were performed after gating on CD19+ cells. TLR expression analysisSMZL cells were analyzed either at the time of blood withdrawal or after thawing. The analysis was performed by flow cytometry using the following antibodies: anti-TLR1 and anti-TLR7 (AbCam); anti-TLR2 (Invitrogen); anti-TLR6 and anti-TLR10 (IMGENEX); anti-TLR8 (DENDRITICS), and anti-TLR9 (eBiosciences). The BD Cytofix/Cytoperm reagent was used for the intracellular staining of TLR7, TLR8 and TLR9. Antibodies against IgD, IgM, CD38 and CD19 were used to detect normal MZ B cells in spleen samples, as previously described. 7-AminoActinomycin D (7-AAD, BD Pharmingen™) was used for the exclusion of nonviable cells in flow cytometric assays. All flow cytometric analyses were performed on a FC-500 (Beckman Coulter) or on a FACSAria II (Becton Dickinson). Cell culture and functional studiesSMZL cells were either unstimulated or stimulated with specific TLR ligands (Online Supplementary Methods). Collection was performed either after 24 hours for CD86 (BD Pharmingen) and CD25 (Beckman Coulter) flow cytometry analysis, or after 48 hours to assess cell proliferation (Ki67 staining, BD Biosciences), apoptosis (Annexin V and Propidium Iodide, Bender Med Systems) and viability (CellTiter-Glo Luminescent Cell Viability Assay, Promega). The IRAK1/4 inhibitor I (Sigma) was used at the concentration of 3 μM 30 minutes before TLR stimulation. The MyD88 inhibitory peptide and control peptide (Novus Biologicals) were used at the concentration of 100 μM. Molecular studiesi. Immunogenetic analysis. PCR amplification and sequence analysis of IGHV-IGHD-IGHJ gene rearrangements was performed as previously described. 20 ii. Qualitative assessment of TLR1-10 and TIR8 expression b...

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Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients

Cited by 78 publications

References 50 publications

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Differential microRNA Profiles and Their Functional Implications in Different Immunogenetic Subsets of Chronic Lymphocytic Leukemia

Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation

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