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

Abstract

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 C1/BN2/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 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.

Molecular profiling in diffuse large B‐cell lymphoma: why so many types of subtypes?

“…Other mutations enriched in the BN2 cluster appear to activate NFKB; these include loss of TNFAIP3, gain of BCL10 and 3ʹ-untranslated region (3ʹUTR) mutation (leading to enhanced expression) of NFKBIZ. 62 Many of these genetic alterations, especially NOTCH2 mutation, are reminiscent of marginal-zone lymphoma (MZL). 63,64 It is tempting to speculate that these lymphomas arise from transformation of an underlying MZL (Fig 6).…”

“…Interestingly, transcriptional signatures of NOTCH activation were not identified in these tumours, 37,40 suggesting that the activating NOTCH2 mutations may exert their effect at a specific stage of lymphoma development. Other mutations enriched in the BN2 cluster appear to activate NFKB; these include loss of TNFAIP3, gain of BCL10 and 3ʹ‐untranslated region (3ʹUTR) mutation (leading to enhanced expression) of NFKBIZ 62 . Many of these genetic alterations, especially NOTCH2 mutation, are reminiscent of marginal‐zone lymphoma (MZL) 63,64 .…”

Genetic Subgroups Inform on Pathobiology in Adult and Pediatric Burkitt Lymphoma

“…For MYD88 , the L273P hotspot mutations were considered in clustering even if the number of patients harboring these mutations did not meet the minimal cut-off threshold resulting from the low number of MCD DLBCL patients present in the cohort. In addition, non-coding mutations in 3’ UTR of NFKBIZ were also included in the feature matrix to facilitate separation of DLBCL patients and their classification 53, 56 .…”