Non-coding NFKBIZ 3′ UTR mutations promote cell growth and resistance to targeted therapeutics in diffuse large B-cell lymphoma

Amplifications and non-coding 3′ UTR mutations affecting NFKBIZ have been identified as recurrent genetic events in diffuse large B-cell lymphoma (DLBCL). We confirm the prevalence and pattern of NFKBIZ 3′ UTR mutations in independent cohorts and determine they are enriched in the ABC subtype as well as the recently described novel BN2/C1/NOTCH2 classes of DLBCL. Presently, the effects of and mechanism by which non-coding mutations can act as cancer drivers has been relatively unexplored. Here, we provide a functional characterization of these non-coding NFKBIZ 3′ UTR mutations. We demonstrate that the resulting elevated expression of IκB-ζ confers growth advantage in DLBCL cell lines and primary germinal center B-cells as well as nominate novel IκB-ζ target genes with potential therapeutic implications. The limited responses to targeted treatments in DLBCL, particularly those targeting the NF-κB axis, led us to investigate and confirm that NFKBIZ 3′ UTR mutations affect response to therapeutics and suggest it may be a useful predictive biomarker. Statement of Significance Through functional characterization we reveal that non-coding NFKBIZ 3′ UTR mutations are a common driver in DLBCL, and mutation status may be a relevant biomarker to predict poor response to therapeutics targeting the NF-κB pathway. ### Competing Interest Statement C.S. has performed consultancy for Seattle Genetics, Curis Inc., Roche, AbbVie, Juno Therapeutics and Bayer, and has received research funding from Bristol-Myers Squibb, Epizyme and Trillium Therapeutics Inc. R.D.M, D.W.S. and C.S. are co-inventors on patents using genetics and gene expression features to classify lymphomas.