IκB Kinase β (IKBKB) Mutations in Lymphomas That Constitutively Activate Canonical Nuclear Factor κB (NFκB) Signaling

Kai, Xin; Chellappa, Vasant; Donado, Carlos; Reyon, Deepak; Sekigami, Yurie; Ataca, Dalya; Louissaint, Abner; Mattoo, Hamid; Joung, J. Keith; Pillai, Shiv

doi:10.1074/jbc.m114.598763

Cited by 21 publications

(15 citation statements)

References 34 publications

(37 reference statements)

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“…We see mutations in oncogenes and tumor-suppressor genes in HepG2, such as NRAS (Pylayeva-Gupta et al 2011), STK11/LKB1 (Zhou et al 2014), and PREX2 (Berger et al 2012;Yang et al 2016), as well as in the Wnt-pathway gene CTNNB1 due to the presence of either HepG2-specific protein-altering changes or small-scale structural changes (Table S5, Table S6, Dataset 1, Dataset 4, Supplemental Data). Moreover, we also identified mutations in genes recently found to play critical roles in driving cancer such as CDK12 (Paculová and Kohoutek 2017) and IKBKB (Xia et al 2012;Kai et al 2014). These mutations also implicate the dis-regulation of their associated molecular pathways in HepG2.…”

Section: Discussionmentioning

confidence: 99%

“…The gene overlap between HepG2 PPA and the Sanger Cancer Gene Census is 19 (Table S6). HepG2 PPA variants include oncogenes and tumor suppressors such as NRAS (Pylayeva-Gupta et al 2011), STK11/LKB1 (Zhou et al 2014), and PREX2 (Berger et al 2012;Yang et al 2016) as well as other genes recently found to play critical roles in driving cancer such as CDK12 (Paculová and Kohoutek 2017) and IKBKB (Xia et al 2012;Kai et al 2014). RP1L1, which was recently found to be significantly mutated in hepatocellular carcinoma (Cancer Genome Atlas Research Network 2017) is also present among the PPA variants.…”

Section: Snvs and Indelsmentioning

confidence: 99%

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Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

Zhou

Greer

Spies

et al. 2018

Preprint

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HepG2 is one of the most widely used human cell lines in biomedical research and one of the main cell lines of ENCODE. Although the functional genomic and epigenomic characteristics of HepG2 are extensively studied, its genome sequence has never been comprehensively analyzed and higher-order structural features of its genome beyond its karyotype were only cursorily known. The high degree of aneuploidy in HepG2 renders traditional genome variant analysis methods challenging and partially ineffective. Correct and complete interpretation of the extensive functional genomics data fromHepG2 requires an understanding of the cell line's genome sequence and genome structure. We performed deep whole-genome sequencing, mate-pair sequencing and linked-read sequencing to identify a wide spectrum of genome characteristics in HepG2: copy numbers of chromosomal segments, SNVs and Indels (both corrected for copynumber), phased haplotype blocks, structural variants (SVs) including complex genomic rearrangements, and novel mobile element insertions. A large number of SVs were phased, sequence assembled and experimentally validated. Several chromosomes show striking loss of heterozygosity. We re-analyzed HepG2 RNA-Seq and wholegenome bisulfite sequencing data for allele-specific expression and phased DNA methylation. We show examples where deeper insights into genomic regulatory complexity could be gained by taking knowledge of genomic structural contexts into account. Furthermore, we used the haplotype information to produce an allele-specific CRISPR targeting map. This comprehensive whole-genome analysis serves as a resource for future studies that utilize HepG2.

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Section: Discussionmentioning

confidence: 99%

Section: Snvs and Indelsmentioning

confidence: 99%

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

Zhou

Greer

Spies

et al. 2018

Preprint

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“…The NFκB pathway is required for normal marginal zone B cell development (Cariappa et al, 2000;Xie et al, 2007). In the study by Kai et al, the introduction of heterozygous and homozygous IKKβ K171E mutations into the human Burkitt's lymphoma BJAB cells by TALEN mutagenesis resulted in constitutive activation of the NFκB pathway (Kai et al, 2014). Moreover, K171E IKBKB knock-in BJAB cells were more resistant to apoptosis, as demonstrated by a significant increase in BCL2 expression (Kai et al, 2014).…”

Section: Lymphoid Disordersmentioning

confidence: 96%

“…Given that ZFN-, TALEN-and CRISPR-based mutagenesis offers the possibility of generating heterozygous and homozygous knock-ins, genome editing technology is a valuable tool for deciphering the impact of a gene mutation. Kai et al have used TALEN-based mutagenesis to study the K171E and K171T mutations in the IκB kinaseβ (IKKβ) protein that are found in splenic marginal zone lymphomas and multiple myeloma (Kai et al, 2014). IKKβ, encoded by the IKBKB gene, is the critical activating kinase in the canonical nuclear factor κB (NFκB) pathway (Rossi et al, 2011;Rossi et al, 2012;Ukaji and Umezawa, 2014).…”

Section: Lymphoid Disordersmentioning

confidence: 99%

Application of genome editing technologies to the study and treatment of hematological disease

Pellagatti

Dolatshad

Yip

et al. 2016

Advances in Biological Regulation

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“…Aberrant NF-kB signaling has been described in various cancers and immune diseases. Gene variants of IKKb have been associated with colorectal cancer (12), lymphomas, multiple myeloma (13), and combined immunodeficiency (14). Previous work has also identified variants of MYD88 and TNFRSF11A that promote constitutive activation of NF-kB (15,16).…”

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confidence: 99%

A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis

Torices

Álvarez-Rodríguez

Grande

et al. 2015

The Journal of Immunology

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Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-κB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-κB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-κB target genes (TRAIL, TNF-α, cIAP-1, IL8) and blocks activation of a NF-κB–luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-κB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-κB and the secretion of TNF-α in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-κB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA.

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IκB Kinase β (IKBKB) Mutations in Lymphomas That Constitutively Activate Canonical Nuclear Factor κB (NFκB) Signaling

Cited by 21 publications

References 34 publications

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

Application of genome editing technologies to the study and treatment of hematological disease

A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis

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