BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas

Qu, Yan; Huang, Yuanxue; Watkins, A. James; Kocialkowski, Sylvia; Zeng, Naiyan; Hamoudi, Rifat; Isaacson, Peter G.; Leval, Laurence de; Wotherspoon, A.C.; Du, Ming

doi:10.3324/haematol.2011.054080

Cited by 91 publications

(75 citation statements)

References 22 publications

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“…[Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] mapping of CN-LOH on 17q allowed the identification of CD79A and CD79B mutations in 15% of WM in our study, mutation identified in WM that was not reported previously by whole exome sequencing [7].Recently, somatic mutation on CD79A and CD79B genes have been identified in ABC lymphoma in nearly 20% of cases, but rarely in other DLBCLs, in Burkitt's lymphoma or in marginal zone lymphoma [13,15]. Interestingly, the point mutations in ABC DLBCLs changed the N-terminal tyrosine of the CD79B ITAM to a different amino acid, similar to that we have observed in WM.…”

Section: Discussionmentioning

confidence: 63%

“…Exons 5-8 of TP53 gene were amplified from genomic DNA by PCR using the HotStar HiFidelity Polymerase KitV R (Qiagen, CA) with the following intronic forward and reverse primers for TP53: 5'-TTCCTCTTCCTGCAGTACTC-3', 5'-AGTTGCAAACCAGACCTCAG-3', 5'-AGGTTGGCTCTGACTGTACC-3', 5'-CTTGTCCTGCTTGCTTACCTC-3'. MYD88, CD79A, CD79B and exons 8-9 of c-CBL were amplified as previously described [13][14][15]. The purified PCR products were directly sequenced in both directions using BigDyeV R Terminator Cycle Sequencing Kit (Applied Biosystems) and analyzed on the Applied Biosystems 3130xl Genetic Analyzer.…”

Section: Gene Mutations Analysismentioning

confidence: 99%

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Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

et al. 2013

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SNP array (SNPa) was developed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) without copy number changes, CN-LOH. We aimed to identify novel genomic aberrations using SNPa in 31 WM with paired samples. Methylation status and mutation were analyzed on target genes. A total of 61 genetic aberrations were observed, 58 CNA (33 gains, 25 losses) in 58% of patients and CN-LOH in 6% of patients. The CNA were widely distributed throughout the genome, including 12 recurrent regions and identified new cryptic clonal chromosomal lesions that were mapped. Gene set expression analysis demonstrated a relationship between either deletion 6q or gain of chromosome 4 and alteration of gene expression profiling. We then studied methylation status and sought for mutations in altered regions on target genes. We observed methylation of DLEU7 on chromosome 13 in all patients (n 5 12) with WM, and mutations of CD79B/CD79A genes (17q region), a key component of the BCR pathway, in 15% of cases. Most importantly, higher frequency of 3 CNA was observed in symptomatic WM. In conclusion, this study expands the view of the genomic complexity of WM, especially in symptomatic WM, including a potentially new mechanism of gene dysfunction, acquired uniparental disomy/CN-LOH. Finally, we have identified new potential target genes in WM, such as DLEU7 and CD79A/B. Am. J.

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Section: Discussionmentioning

confidence: 63%

Section: Gene Mutations Analysismentioning

confidence: 99%

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

et al. 2013

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“…2 Recent studies have reported mutations affecting the NF-κB signaling pathway in a proportion of SMZL cases. [3][4][5] Such mutations have been identified in both the B-cell Receptor (BCR) and Toll-Like Receptor (TLR) signaling pathways e.g. CARD11 and MYD88 gene mutations, respectively, 3,[5][6][7][8][9] implicating immune signaling in the natural history of selected SMZL cases.…”

Section: Introductionmentioning

confidence: 99%

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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“…Antigenic stimulation through immune receptors such as BCR and TLR, has been postulated to be involved in the development of CLL and SMZL, [40][41][42] in addition expression of functional TLRs and signaling molecules were described in CLL, 28,29,43 and SMZL. 7 Mutations in genes that are activated through BCR signaling or toll-like and interleukin signaling were associated with constitutive activation of TLR-signaling and a higher histological score in SMZL.…”

Section: Discussionmentioning

confidence: 99%

The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

et al. 2017

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Microenvironmental regulation in lymphoid tissues is essential for the development of chronic lymphocytic leukemia. We identified cellular and molecular factors provided by the splenic marginal zone (MZ), which alter the migratory and adhesive behavior of leukemic cells. We used the Cxcr5 ¡/¡ Em-Tcl1 leukemia mouse model, in which tumor cells are excluded from B cell follicles and instead accumulate within the MZ. Genes involved in MZ B cell development and genes encoding for adhesion molecules were upregulated in MZ-localized Cxcr5 ¡/¡ Em-Tcl1 cells. Likewise, surface expression of the adhesion and homing molecules, CD49d/VLA-4 and CXCR7, and of NOTCH2 was increased. In vitro, exposing Em-Tcl1 cells or human CLL cells to niche-specific stimuli, like B cell receptor-or Toll-like receptor ligands, caused surface expression of these molecules characteristic for a follicular or MZ-like microenvironment, respectively. In vivo, inhibition of VLA-4-mediated adhesion and CXCL13-mediated follicular homing displaced leukemic cells not only from the follicle, but also from the MZ and reduced leukemia progression. We conclude that MZ-specific factors shape the phenotype of leukemic cells and facilitate their niche-specific retention. This strong microenvironmental influence gains pathogenic significance independent from tumor-specific genetic aberrations.

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BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas

Cited by 91 publications

References 22 publications

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

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

The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

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