Constitutive Nuclear Factor κB Activity Is Required for Survival of Activated B Cell–like Diffuse Large B Cell Lymphoma Cells

By R. Davis, K. Brown, U. Siebenlist, Louis Staudt. Journal of Experimental Medicine, 2001

1,153 citations recorded by the source corpus.

Gene expression profiling has revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two distinct diseases. Patients with one DLBCL subtype, termed activated B cell–like (ABC) DLBCL, have a distinctly inferior prognosis. An untapped potential of gene expression profiling is its ability to identify pathogenic signaling pathways in cancer that are amenable to therapeutic attack. The gene expression profiles of ABC DLBCLs were notable for the high expression of target genes of the nuclear factor (NF)-κB transcription factors, raising the possibility that constitutive activity of the NF-κB pathway may contribute to the poor prognosis of these patients. Two cell line models of ABC DLBCL had high nuclear NF-κB DNA binding activity, constitutive IκB kinase (IKK) activity, and rapid IκBα degradation that was not seen in cell lines representing the other DLBCL subtype, germinal center B-like (GCB) DLBCL. Retroviral transduction of a super-repressor form of IκBα or dominant negative forms of IKKβ was toxic to ABC DLBCL cells but not GCB DLBCL cells. DNA content analysis showed that NF-κB inhibition caused both cell death and G1-phase growth arrest. These findings establish the NF-κB pathway as a new molecular target for drug development in the most clinically intractable subtype of DLBCL and demonstrate that the two DLBCL subtypes defined by gene expression profiling utilize distinct pathogenetic mechanisms.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6cfd603db354ba74dc824ffec260df073bca94f4

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Citations in the corpus

Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. (2007, methodology): “These same genes were downregulated in MM cell line EJM upon retroviral expression of the IkBa super-repressor, a specific inhibitor of classical NF-kB signaling (Davis et al., 2001), which was toxic to both L363 and EJM cell lines (data not shown).”
NF‐κB and the link between inflammation and cancer (2012, background): “The CARD11 gene was found to be mutated in a subset of ABC-DLBCL (96).”
A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications (2020, background): “NF-kB target genes were highly expressed in MCD but not EZB, as expected (Davis et al., 2001), but were also high in BN2 and ST2.”
Germinal centres: role in B-cell physiology and malignancy (2008, background): “Finally, whereas the constitutive activity of the NF-κB signalling pathway has been implicated in DLBCL pathogenesi”
Mutations of multiple genes cause deregulation of NF-kB in diffuse large B-cell lymphoma (2009, neutral): “ABC-DLBCL Non-GC/NC-DLBCL Biallelic deletion Mutation plus deletion Biallelic mutation Heterozygous mutation Monoallelic deletion Normal Mutated Deleted Normal Nonsense mutations (12) Frameshift deletions (7) Frameshift insertions (5) Splice site mutations (2)”
To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis (2003, background): “…lymphoma (DLBCL), acute lymphoblastic leukemia, chronic myelogenous leukemia, ATL and breast cancer among many others (Bargou et al., 1997; Nakshatri et al., 1997; Sovak et al., 1997; Cogswell et al., 2000; Kordes et al., 2000; Davis et al., 2001; Hinz et al., 2001; Kalaitzidis et al., 2002).”
Circuitry of nuclear factor κB signaling (2006, background): “However, the regulation of these cellular processes by NF-kB transcription factors is of relevance to human health: inappropriate upregulation of NFkB in B-cell lymphomas has been shown to provide essential pro-survival signals in the context of highly proliferating cells (55).”
Mechanisms of B-cell lymphoma pathogenesis (2005, background): “For example, the recognition that a subtype of diffuse large B-cell lymphoma expresses an active NF-κB signature led to the identification of a dependency of these lymphomas on constitutive NF-κB activity — making this transcription factor an attractive target for therap”
Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways (2008, background): “Whereas the NF- B pathway is activated in ABC DLBCLs by cell autonomous mechanisms (19, 21), GCB DLBCLs may use REL amplification to enhance the NF- B response to signals from the microenvironment.”
BIC and miR‐155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas (2005, result): “∗Note that L591 was analysed on a separate blot, to compare it with the other HL cell lines DEV was also analysed on this blot the ABC-like DLBCL phenotype [ 25 ].”