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Graded constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironment dependence [M002]

ABSTRACT: Aberrant activation of NF-κB transcription factors is a hallmark of human lymphoma. Many lymphoma- as well as microenvironment-associated alterations mediating enhanced NF-κB signaling occur upstream of the IκB Kinase complex and its key kinase IKK2, therefore affecting additional pathways. Here, we specifically investigated the effects of graded canonical NF-κB activation in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant (IKK2ca). Strong canonical NF-κB signaling drives an early expansion of B1a cells, culminating in lethal lymphomagenesis with complete penetrance. These B cell malignancies resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) with respect to disease course, gene expression and stereotypic B cell receptor clonality. Mice with less pronounced canonical NF-κB activation presented delayed, more heterogeneous lymphomagenesis with lower penetrance, highlighting NF-κB dose-dependent effects. Mechanistically, we show that constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and strongly synergize with TCL1 overexpression, resulting in a severely accelerated and aggravated CLL-like disease. In addition, strong constitutive NF-κB activation overcomes the critical dependency of TC1tg lymphoma cells on obligate environmental maintenance signals. In conclusion, we provide direct in vivo proof for canonical NF-κB signals as an oncogenic driver in an animal model, and demonstrate reduced tumor microenvironment dependency as a key NF-κB-mediated mechanism in lymphomagenesis. Our findings underscore the pivotal role of this pathway in human SLL/CLL and its potential as a therapeutic target, particularly for aggressive/refractory disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE289016 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-κB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB–inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-κB pathway in B lymphoproliferative disease. This study compares nine t(11;18)-positive MALT lymphomas (8 from the stomach and 1 from lung) and eight translocation negative MALT lymphomas (all from the stomach) using gene set enrichment analysis (GSEA). All cases were subjected to Affymetrix U133A and U133B microarray analysis. The cases used in this study are the same cases used for the study by Hamoudi et al. (2010) entitled "Differential expression of NF-kB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism" with GEO reference number: GSE18736 and PubMed ID: http://www.ncbi.nlm.nih.gov/pubmed/20520640 All cases were subjected to non-specific filtering to eliminate non-variant probes, then the U133A and U133B probes were collapsed and the collapsed set was subjected to GSEA using the NF-kB target gene set as described in Hamoudi et al. (2010) study mentioned above. The 34 samples in this study are identical to the ones done in the previous series except that the gene set enrichment was done on just those 34 samples and not the complete set.

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Graded constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironment dependence [M002]

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