An Oncogenic Role for Alternative NF-κB Signaling in DLBCL Revealed upon Deregulated BCL6 Expression

• Genetic loss of TRAF3 is associated with alternative NF-κB activation in DLBCL
• Constitutive alternative NF-κB activity promotes B cell and plasma cell hyperplasia
• NF-κB-enforced terminal B cell differentiation is repressed by BCL6 in vivo
• Alternative NF-κB signaling cooperates with BCL6 to induce DLBCL in a mouse model

SummaryDiffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF-κB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-κB pathway in DLBCL development.

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