NF-κB p50 (nfkb1) contributes to pathogenesis in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia

Chen, Timothy L.; Tran, Minh; Lakshmanan, Aparna; Harrington, Bonnie K.; Gupta, Nikhil; Goettl, Virginia M.; Lehman, Amy; Trudeau, Stephen J.; Lucas, David M.; Johnson, Amy J.; Byrd, John C.; Hertlein, Erin

doi:10.1182/blood-2017-01-761130

Cited by 10 publications

(7 citation statements)

References 17 publications

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“…5a–c; Supplementary Table 5). Consistent with the key role of transcription factors (TFs) in DNAme patterning in CLL 4 , we identified gene promoter enrichment for binding motifs of TFs with established roles in CLL progression at sites surrounding low epimutation CpGs (±25bp), including NF-KB1 12 and MYBL1 13 , a TF involved in c-Myc activation in lymphoid neoplasms 14 (Fig. 1i, right ; Extended Data Fig.…”

supporting

confidence: 70%

Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia

Gaiti

Chaligné

et al. 2019

Nature

208

212

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Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer 1 . Chronic lymphocytic leukemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution with therapy 2 , 3 . The CLL epigenome is also an important disease-defining feature 4 , 5 , and growing CLL populations diversify through stochastic DNA methylation (DNAme) changes – epimutations 6 . However, previous studies based on bulk DNAme sequencing could not answer whether epimutations affect CLL populations homogenously. To measure epimutation rate at single-cell resolution, we applied multiplexed single-cell reduced representation bisulfite sequencing (MscRRBS) to healthy donors B cell and CLL patient samples. We observed that the common clonal CLL origin results in consistently elevated epimutation rate, with low cell-to-cell epimutation rate variability. In contrast, variable epimutation rates across normal B cells reflect diverse evolutionary ages across the B cell differentiation trajectory, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed high-resolution lineage reconstruction with single-cell data, applicable directly to patient samples. CLL lineage tree shape revealed earlier branching and longer branch lengths than normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. MscRRBS integrated with single-cell transcriptomes and genotyping confirmed that genetic subclones map to distinct clades inferred solely based on epimutation information. Lastly, to examine potential lineage biases during therapy, we profiled serial samples during ibrutinib-associated lymphocytosis, and identified clades of cells preferentially expelled from the lymph node with therapy, marked by distinct transcriptional profiles. The single-cell integration of genetic, epigenetic and transcriptional information thus charts CLL’s lineage history and its evolution with therapy.

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supporting

confidence: 70%

Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia

Gaiti

Chaligné

et al. 2019

Nature

208

212

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“…Previous researches have shown that NF‐κB1, one of the critical genes implicated in the NF‐κB signalling pathway, plays an important role in ALI. 15 , 16 , 17 NF‐κB can also mediate the expression of CXCR1, 18 and is a potential therapeutic target for ALI. 19 , 20 , 21 Therefore, a hypothesis was proposed that KLF2 might inhibit the transcriptional activity of NF‐κB to affect the NET‐induced TRALI.…”

Section: Resultsmentioning

confidence: 99%

“… 14 Moreover, studies have indicated that nuclear factor kappa‐B1 (NF‐κB1), one of the major genes of the NF‐κB pathway, can affect acute lung injury. 15 , 16 , 17 NF‐κB can mediate the expression of chemokine (C‐X‐C motif) receptor 1 (CXCR1), as CXCR1 is a potential therapeutic target for acute lung injury. 18 , 19 , 20 , 21 More importantly, accumulating evidence on murine models of TRALI 22 , 23 , 24 has suggested the feasibility of developing mouse models to investigate TRALI.…”

Section: Introductionmentioning

confidence: 99%

MiR‐144‐induced KLF2 inhibition and NF‐kappaB/CXCR1 activation promote neutrophil extracellular trap–induced transfusion‐related acute lung injury

Liu

et al. 2021

J Cellular Molecular Medi

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“…Since its discovery about thirty years ago, tremendous progress has been made in understanding the functions and signaling networks of NF-κB in physiological and pathophysiological processes, including inflammation, immunity and cell survival [1]. In line with its central roles in multi-layered physiological functions, deregulated NF-κB activity is found in a large number of diseases, especially in large variety of human malignancies [[2], [3], [4]]. For instance, it has been demonstrated that hyperactivation of NF-κB signaling elicits promotion of migration, invasion, apoptotic resistance and induction of angiogenesis in cancers via transcriptional upregulation of multiple NF-κB downstream genes, such as matrix metalloproteinase (MMPs), B-cell lymphoma (BCLs) and vascular endothelial growth factor (VEGF) [[5], [6], [7], [8]].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of PIMREG promotes breast cancer aggressiveness via constitutive activation of NF-κB signaling

et al. 2019

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Background It is well-established that activation of nuclear factor-kappa B (NF-κB) signaling plays important roles in cancer development and progression. However, the underlying mechanism by which the NF-κB pathway is constitutively activated in cancer remains largely unclear. The present study aimed to investigate the effect of PICALM interacting mitotic regulator (PIMREG) on sustaining NF-κB activation in breast cancer. Methods The underlying mechanisms in which PIMREG-mediated NF-κB constitutive activation were determined via immunoprecipitation, EMSA and luciferase reporter assays. The expression of PIMREG was examined by quantitative PCR and western blotting analyses and immunohistochemical assay. The effect of PIMREG on aggressiveness of breast cancer cell was measured using MTT, soft agar clonogenic assay, wound healing and transwell matrix penetration assays in vitro and a Xenografted tumor model in vivo . Findings PIMREG competitively interacted with the REL homology domain (RHD) of NF-κB with IκBα, and sustained NF-κB activation by promotion of nuclear accumulation and transcriptional activity of NF-κB via disrupting the NF-κB/IκBα negative feedback loop. PIMREG overexpression significantly enhanced NF-κB transactivity and promoted the breast cancer aggressiveness. The expression of PIMREG was markedly upregulated in breast cancer and positively correlated with clinical characteristics of patients with breast cancer, including the clinical stage, tumor-node-metastasis classification and poorer survival. Interpretation PIMREG promotes breast cancer aggressiveness via disrupting the NF-κB/IκBα negative feedback loop, which suggests that PIMREG might be a valuable prognostic factor and potential target for diagnosis and therapy of metastatic breast cancer. Fund The science foundation of China, Guangdong Province, Guangzhou Education System, and the Science and Technology Program of Guangzhou.

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NF-κB p50 (nfkb1) contributes to pathogenesis in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia

Abstract: 19. Riether C, Schürch CM, Bührer ED, et al. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia.

Cited by 10 publications

References 17 publications

Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia

Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia

MiR‐144‐induced KLF2 inhibition and NF‐kappaB/CXCR1 activation promote neutrophil extracellular trap–induced transfusion‐related acute lung injury

Overexpression of PIMREG promotes breast cancer aggressiveness via constitutive activation of NF-κB signaling

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