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

Zachary R. Hunter, Lian Xu, Nickolas Tsakmaklis, Maria G. Demos, Amanda Kofides, Cristina Jimenez, Gloria G. Chan, Jiaji Chen, Xia Liu, Manit Munshi, Joshua Gustine, Kirsten Meid, Christopher J. Patterson, Guang Yang, Toni Dubeau, Mehmet K. Samur, Jorge J. Castillo, Kenneth C. Anderson, Nikhil C. Munshi and Steven P. Treon

Key Points

  • Mutations affecting NF-κB, epigenomic regulation, or DNA damage repair were identified in MYD88 wild-type WM.

  • NF-κB pathway mutations were downstream of BTK, and many overlapped with those found in aggressive B-cell lymphomas.


Activating MYD88 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 MYD88-mutated (MYD88MUT) WM patients, but shows lower activity in MYD88 wild-type (MYD88WT) disease. MYD88WT 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 MYD88WT patients and compared findings with WM patients with MYD88MUT disease. We identified somatic mutations predicted to activate NF-κB (TBL1XR1, PTPN13, MALT1, BCL10, NFKB2, NFKBIB, NFKBIZ, and UDRL1F), impart epigenomic dysregulation (KMT2D, KMT2C, and KDM6A), or impair DNA damage repair (TP53, ATM, and TRRAP). 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 MYD88WT WM was identified, although most differentially expressed genes overlapped with MYD88MUT 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 MYD88WT WM patients. The findings depict genomic and transcriptional events associated with MYD88WT WM and provide mechanistic insights for disease transformation, decreased ibrutinib activity, and novel drug approaches for this population.

  • Submitted June 27, 2018.
  • Accepted October 5, 2018.
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