Significance of oncogenic MYD88 and CD79B mutations in B-cell lymphomas

Abstract

Gain-of-function mutations of MYD88 and CD79B genes have been reported to lead to constitutive activation of the nuclear factor (NF)-κB pathway, thereby playing an important role in the development of malignant B-cell-type lymphoma. We herein investigated MYD88^L265P and CD79B^Y196 mutations by polymerase chain reaction-based techniques in a total of 141 cases of different types of B-cell lymphoma, and correlated the mutations with B-cell lymphoma category, primary anatomical site of the disease, class of immunoglobulin heavy chain expressed on the cell surface, and rearrangement of the BCL2, BCL6, and MYC genes. As a result, MYD88^L265P mutation was detected in 18 (22%) of 81 cases of diffuse large B-cell lymphoma (DLBCL), 2 (100%) of 2 cases of lymphoplasmacytic lymphoma, and 1 (5%) of 20 cases of unclassifiable B-cell lymphoma. CD79B^Y196 mutation was found in 14 (17%) DLBCL cases, and 9 DLBCL cases carried both mutations, but no mutation was found in follicular lymphoma, marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), or mantle cell lymphoma. MYD88^L265P/CD79B^Y196 mutations were significantly associated with DLBCL of the non-germinal center B-cell-like (non-GCB) subtype, and the mutations were preferentially found in DLBCL that developed in particular extranodal sites, e.g. brain, testis, and nasal cavity/paranasal sinuses. Expression of the μ heavy chain was associated with MYD88^L265P/CD79B^Y196 mutations, and that of the γ or α heavy chain was associated with the lack of mutation and GCB phenotype. Of 23 cases with MYD88^L265P/CD79B^Y196 mutations, 7 had rearrangement of either BCL2, BCL6, or MYC, and one had both BCL2 and BCL6 mutations, suggesting that MYD88^L265P/CD79B^Y196 mutations and BCL2/BCL6/MYC rearrangements are not necessarily exclusive. As MYD88/CD79B mutations were found to correlate with the response to Bruton's tyrosine kinase inhibitor ibrutinib, detection of mutations will become necessary to select appropriate targeting agents in the treatment of B-cell lymphoma.