Abstract
Activating mutations in CD79 and MYD88 have recently been found in a subset of diffuse large B-cell lymphoma (DLBCL), identifying B-cell receptor and MYD88 signalling as potential therapeutic targets for personalized treatment. Here, we report the prevalence of CD79B and MYD88 mutations and their relation to established clinical, phenotypic and molecular parameters in a large panel of DLBCLs. We show that these mutations often coexist and demonstrate that their presence is almost mutually exclusive with translocations of BCL2, BCL6 and cMYC, or Epstein–Bar virus infection. Intriguingly, MYD88 mutations were by far most prevalent in immune-privileged site-associated DLBCL (IP-DLBCL), presenting in central nervous system (75%) or testis (71%) and relatively uncommon in nodal (17%) and gastrointestinal tract lymphomas (11%). Our results suggest that MYD88 and CD79B mutations are important drivers of IP-DLBCLs and endow lymphoma-initiating cells with tissue-specific homing properties or a growth advantage in these barrier-protected tissues.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic class of lymphomas comprising molecularly distinct subtypes that differ in gene expression profile, oncogenic aberrations, clinical presentation and outcome.[1,2] A current gene expression profile-based molecular classification of DLBCL distinguishes two main subtypes: activated B-cell-like (ABC) lymphoma and germinal centre B-cell-like lymphoma
The antiapoptotic nuclear factor-kB signalling pathway is constitutively active in ABC-type DLBCLs as a result of oncogenic CARD11 mutations and/or of CD79 mutations causing chronic active B-cell receptor (BCR) signalling enhanced by inactivation of A20.3–6 In addition, somatically acquired mutations in MYD88, an adaptor protein that mediates toll-like receptor and interleukin-1 receptor signalling were recently shown to control cell survival in this lymphoma type by promoting NF-kB and Janus Kinase (JAK)/ Signal transducer and activator of transcription 3 (STAT3) signalling
The above findings are of great interest as they identify BCR and MYD88 signalling as potential therapeutic targets and provide a genetic tool to identify patients that may benefit from personalized treatment targeting these pathways
Summary
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic class of lymphomas comprising molecularly distinct subtypes that differ in gene expression profile, oncogenic aberrations, clinical presentation and outcome.[1,2] A current gene expression profile-based molecular classification of DLBCL distinguishes two main subtypes: activated B-cell-like (ABC) lymphoma and germinal centre B-cell-like lymphoma. The antiapoptotic nuclear factor-kB signalling pathway is constitutively active in ABC-type DLBCLs as a result of oncogenic CARD11 mutations and/or of CD79 mutations causing chronic active B-cell receptor (BCR) signalling enhanced by inactivation of A20.3–6 In addition, somatically acquired mutations in MYD88, an adaptor protein that mediates toll-like receptor and interleukin-1 receptor signalling were recently shown to control cell survival in this lymphoma type by promoting NF-kB and Janus Kinase (JAK)/ Signal transducer and activator of transcription 3 (STAT3) signalling. These notions prompted us to explore the prevalence of CD79B and MYD88 mutations and their relation to established clinical, phenotypic and molecular parameters in a large panel of DLBCL patients
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