Oncogenic Mutations of MYD88 and CD79B in Diffuse Large B-Cell Lymphoma and Implications for Clinical Practice

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma in adults. Despite the recognition of transcriptional subtypes with distinct functional characteristics, patient outcomes have not been substantially altered since the advent of chemoimmunotherapy (CIT) twenty years ago. Recently, a few pivotal studies added to the disease heterogeneity by describing several activating mutations, which have been associated with disease presentation, B-cell function and behavior, and final outcome. DLBCL arises from antigen exposed B-cells, with the B-cell receptor (BCR) playing a central role. BCR-activity related mutations, such as CD79B and MYD88, are responsible for chronic activation of the BCR in a substantial subset of patients. These mutations, often coexisting in the same patient, have been found in a substantial subset of patients with immune-privileged (IP) sites DLBCLs, and are drivers of lymphoma development conferring tissue-specific homing properties. Both mutations have been associated with disease behavior, including tumor response either to CIT or to BCR-targeted therapy. The recognition of CD79B and MYD88 mutations will contribute to the heterogeneity of the disease, both in recognizing the BCR as a potential therapeutic target and in providing genetic tools for personalized treatment.

Comparative Molecular Analysis of Primary Central Nervous System Lymphomas and Matched Vitreoretinal Lymphomas by Vitreous Liquid Biopsy

“…Both cases had complete CDKN2A deletions, an alteration we have observed to be highly recurrent in VRL patients and which is a promising genomic biomarker with potential clinical utility that warrants further investigation [ 42 ]. MYD88 , a gene encoding for an NF-kB pathway component, is also recurrent in B-cell lymphomas [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ] and was found here as a truncal activating mutation in Case 2. Interestingly, Case 1 harbored a MYD88 p.A221T mutation with a highly subclonal status in the brain tissue sample (8% variant fraction).…”

Cytologic and Molecular Diagnostics for Vitreoretinal Lymphoma: Current Approaches and Emerging Single-Cell Analyses

“…For example, ibrutinib, a small-molecule drug that targets Bruton's tyrosine kinase (BTK), can be considered for the treatment of patients with VRL who have an underlying MYD88 L265P mutation, which is known to trigger lymphomagenesis via BTK activation. Although there is currently no clear correlation between MYD88 mutational profiles and ibrutinib response (Visco et al, 2020 ), several studies have shown clinical responses to ibrutinib treatment in some DLBCL patients with an MYD88 L265P mutation (Deng et al, 2017 ; Soussain et al, 2019 ). MYD88 L265P mutations frequently co-occur in DLBCL patients who also harbor a mutation of CD79B, a subunit that is important for transducing BCR signaling.…”

“…The hypersensitivity of MYD88/CD79B double-mutant DLBCLs to ibrutinib treatment is probably due to the co-inhibition of BTK and CD79B-dependent BCR signaling. Taken together, oncogenic mutations of MYD88 and CD79B in DLBCL have major implications for clinical practice (Visco et al, 2020 ) and may provide useful genetic tools for personalized targeted therapies.…”

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“…For example, ibrutinib, a small-molecule drug that targets Bruton's tyrosine kinase (BTK), can be considered for the treatment of patients with VRL who have an underlying MYD88 L265P mutation, which is known to trigger lymphomagenesis via BTK activation. Although there is currently no clear correlation between MYD88 mutational profiles and ibrutinib response (Visco et al, 2020), several studies have shown clinical responses to ibrutinib treatment in some DLBCL patients with an MYD88 L265P mutation (Deng et al, 2017;Soussain et al, 2019). MYD88 L265P mutations frequently co-occur in DLBCL patients who also harbor a mutation of CD79B, a subunit that is important for transducing BCR signaling.…”

“…The hypersensitivity of MYD88/CD79B double-mutant DLBCLs to ibrutinib treatment is probably due to the co-inhibition of BTK and CD79B-dependent BCR signaling. Taken together, oncogenic mutations of MYD88 and CD79B in DLBCL have major implications for clinical practice (Visco et al, 2020) and may provide useful genetic tools for personalized targeted therapies.…”