MYD88 was the most frequently altered gene in our cohort, with potentially clinically relevant hotspot gain-of-function mutations identified in 71% of diffuse large B-cell lymphomas and 25% of marginal zone lymphomas.
Mutation of the MYD88 gene has recently been identified in activated B-cell-like diffuse cell lymphoma and enhanced Janus kinase/signal transducer and activator of transcription (JAK-STAT) and nuclear factor κB (NF-κB) signaling pathways.
In order to evaluate whether the presence of the recently described MYD88L265P mutation in patients with Waldenström's macroglobulinemia (WM) is contributory to SS-associated lymphomagenesis, a quantitative allele-specific PCR method was performed in peripheral blood derived from 90 SS patients as well as in minor salivary gland tissues derived from 12 primary SS patients with or without lymphoma.
IGHV gene features and MYD88L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas.
Myeloid differentiation primary response 88 (MYD88) is a common adaptor protein that is responsible for signaling from several receptors; mutations in this gene may play a role in the pathogenesis of lymphoma.
Individuals with tumors positive for MYD88 mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that MYD88 mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment.
With clinical trials regarding their efficacy rapidly expanding to NHLs, we also discuss potential combinations of immune checkpoint inhibitors with the described targeted chemotherapies of L265P signaling networks, and/or with the above immunological approaches as potential ways of targeting MYD88-mutated lymphomas in the future.
MYD88 mutations were identified in 20 of 29 (69%) clinically, histologically, and molecularly confirmed VRL, including 6 cases of the test cohort initially diagnosed as reactive (3/6) or suspicious (3/6) for lymphoma.
This review discusses the molecular and biological mechanisms underlying MYD88 mutations in LPL/WM, the role of MYD88 mutations as molecular biomarker for the refinement of diagnosis and the improvement classification of LPL/WM, and novel targeted therapeutic strategies for LPL/WM based on the pharmacological manipulation of MYD88 signaling to which this lymphoma is addicted.
Mutations in 2 upstream components of the nuclear factor κB (NF-κB) pathway, CD79B and MYD88, are important information for new target therapy in malignant lymphoma.