NF-κB activation in chronic lymphocytic leukemia: A point of convergence of external triggers and intrinsic lesions

Mansouri, Larry; Papakonstantinou, Nikos; Ntoufa, Stavroula; Stamatopoulos, Kostas; Rosenquist, Richard

doi:10.1016/j.semcancer.2016.07.005

Cited by 75 publications

(72 citation statements)

References 104 publications

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“…NFκB signalling can be blocked by different types of inhibitors, including IKK inhibitors, proteasome inhibitors that block IκB degradation, inhibitors of the nuclear translocation of NFκB subunits and suppressors of NFκB DNA binding (Mansouri et al , ; Zhang et al , ). In CLL, the preclinical activity of several direct and indirect NFκB pathway inhibitors has been reported, including the IKK inhibitors BAY‐117082 (Pickering et al , ), IMD‐0354 (Kanduri et al , ) and BMS‐345541 (Lopez‐Guerra et al , ) and proteasome inhibitors, bortezomib (Faderl et al , ), and curcumin (Everett et al , ).…”

Section: Nfκb Pathwaymentioning

confidence: 99%

Chronic lymphocytic leukaemia genomics and the precision medicine era

2017

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Massive genomic analyses have underscored the diversity of chronic lymphocytic leukaemia (CLL) between patients. Genetic heterogeneity of tumour clones within a patient may fuel tumour evolution. Several recurrently deregulated intra-cellular pathways are candidates for targeted therapies that are very promising and are dramatically changing clinical patients' perspectives. In this review we present an overview of the genetic and epigenetic features of CLL and their clinical and biological implications.

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Section: Nfκb Pathwaymentioning

confidence: 99%

Chronic lymphocytic leukaemia genomics and the precision medicine era

2017

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“…Nfkbie loss cooperates with MYD88 signaling MYD88 codes for an proximal signaling adaptor downstream of IL-1R and mammalian TLRs. Mutations in MYD88, essentially the missense p.L265P mutation, are observed in a wide range of B-cell malignancies 8,10,13,[35][36][37][38][39] . They have been shown to activate the JAK and NF-κB pathways 36 .…”

Section: These In Vitro Data Mirror the In Vivo Results And Indicate mentioning

confidence: 99%

“…We then investigated the impact of Nfkbie deficiency on the proliferative response of splenic and peritoneal B-cell subsets to T-cell independent stimuli, such as TLR agonists. These stimuli are known to induce NF-κB activity in B cells 1,8,[20][21][22]32 . FACS-sorted splenic B-cell subsets, FoB (CD19+B220+CD23+CD21+), MZB (CD19+B220 +CD23lowCD21hi), and B1 (CD19+B220low) cells were stimulated with anti-IgM, LPS, or CpG oligodeoxynucleotides, and cell division was measured by CFSE dilution and cell count after 72 h of culture.…”

Section: Nfkbie-deficient B1a Cells Hyper-proliferate In Response To mentioning

confidence: 99%

“…Aberrant NF-κB activation is frequently observed in several B-cell malignancies [2][3][4][5][6] . This activation can result from interactions with the tumor microenvironment [7][8][9] or as a result of somatic mutations affecting NF-κB family members or upstream signaling components, such as CD79B, BIRC3, CARD11, MYD88, TNFAIP3/A20, or inhibitors of kappa B (IκBs; refs. 3,5,6,[10][11][12][13] ).…”

Section: Introductionmentioning

confidence: 99%

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Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

et al. 2020

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Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.

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“…Except for a suggestively significant p-value in diffuse large B-cell lymphoma (DLBCL) (p=8.47E-4), it had totally insignificant p-values in the other 32 cancers (p>0.42). In fact, a lot of studies have suggested MYD88 as a driver gene for the two cancers (47), (48). The single unique genes of three other cancers had no hit papers by far in PubMed and are subject to validation in the future.…”

Section: Genes Significant Only In An Individual Cancermentioning

confidence: 99%

WITER: A powerful method for the estimation of cancer-driver genes using a weighted iterative regression accurately modelling background mutation rate

Jiang

Zheng

Kwan

et al. 2018

Preprint

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Genomic identification of driver mutations and genes in cancer cells are critical for precision medicine. Due to difficulty in modeling distribution of background mutations, existing statistical methods are often underpowered to discriminate driver genes from passenger genes. Here we propose a novel statistical approach, weighted iterative zero-truncated negative-binomial regression (WITER), to detect cancer-driver genes showing an excess of somatic mutations. By solving the problem of inaccurately modeling background mutations, this approach works even in small or moderate samples. Compared to alternative methods, it detected more significant and cancer-consensus genes in all tested cancers. Applying this approach, we estimated 178 driver genes in 26 different cancers types. In silico validation confirmed 90.5% of predicted genes as likely known drivers and 7 genes unique for individual cancers as likely new drivers. The technical advances of WITER enable the detection of driver genes in TCGA datasets as small as 30 subjects, rescuing more genes missed by alternative tools. Running title: powerful cancer-driver gene detection methodIn the present study, we built a model to predict high-frequency cancer driver potential to use as prior weights, by the random forest trained in a large cancer somatic mutation database, COSMIC (V83). (See details in the supplementary notes). One can also use other methods to produce the prior weights. Tier III: A schedule of integrate independent reference samples to stabilize the regression model for small samplesWhen the sample size is small, it is difficult to build a stable regression model. Note that the key idea of ITER and WITER is to build a prediction model for background passenger genes. When the mutation rates of passenger genes of two cancers are similar, it may be workable to integrate background genes of one cancer into another cancer. We proposed a reference sample strategy for construct a stable ITER or WITER model in small samples. This is carried out at two stages. i. The above ITER or WITER is used to produce p-values for excess of somatic mutations at genes in a reference sample which have enough variants. Genes with p-values less than a very loose cutoff, say FDR 0.3, are then excluded. ii. The somatic mutations of retained genes are integrated with the local small sample and input into ITER or WITER to build a new model. The excess of somatic mutations and corresponding p-values at genes are calculated based on the new model. Curation of cancer-specific predictors of somatic mutationsWe collected 4 types of cancer-specific predictors for somatic mutations, copy number variation (CNV), gene expression, DNA methylation, and chromatin accessibility by ATAC-Seq. All data were produced from TCGA cohorts and the preprocessed data were downloaded from https://xenabrowser.net. The pan-CNVs mapped onto genes were downloaded by the link, https://tcga.xenahubs.net/download/TCGA.PANCAN.sampleMap/Gistic2_CopyNumber_Gistic2 _all_thresholded.by_genes.gz. We then wrote a progr...

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NF-κB activation in chronic lymphocytic leukemia: A point of convergence of external triggers and intrinsic lesions

Cited by 75 publications

References 104 publications

Chronic lymphocytic leukaemia genomics and the precision medicine era

Chronic lymphocytic leukaemia genomics and the precision medicine era

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

WITER: A powerful method for the estimation of cancer-driver genes using a weighted iterative regression accurately modelling background mutation rate

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