Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia.

Activating mutations are present in 95% of Waldenström macroglobulinemia (WM) patients, and trigger NF-κB through BTK and IRAK. The BTK inhibitor ibrutinib is active in mutated ) WM patients, but shows lower activity in wild-type ( ) disease. patients also show shorter overall survival, and increased risk of disease transformation in some series. The genomic basis for these findings remains to be clarified. We performed whole exome and transcriptome sequencing of sorted tumor samples from 18 patients and compared findings with WM patients with disease. We identified somatic mutations predicted to activate NF-κB (, , , , , and ), impart epigenomic dysregulation (, and , or impair DNA damage repair (, , and ). Predicted NF-κB activating mutations were downstream of BTK and IRAK, and many overlapped with somatic mutations found in diffuse large B-cell lymphoma. A distinctive transcriptional profile in WM was identified, although most differentially expressed genes overlapped with WM consistent with the many clinical and morphological characteristics that are shared by these WM subgroups. Overall survival was adversely affected by mutations in DNA damage response in WM patients. The findings depict genomic and transcriptional events associated with WM and provide mechanistic insights for disease transformation, decreased ibrutinib activity, and novel drug approaches for this population.