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

Abstract

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.

CXCR4 S338X clonality is an important determinant of ibrutinib outcomes in patients with Waldenström macroglobulinemia

“…6,7 MYD88 WT patients harbor NF-kB pathway mutations downstream of BTK, and derive minimal benefit from ibrutinib. 8,9 CXCR4 mutations occur nearly exclusively with mutated MYD88 and promote enhanced AKT and extracellular signal-regulated kinase 1/2 activation. 5,10,11 CXCR4 mutations also confer both in vitro and clinical resistance to ibrutinib, particularly nonsense variants such as CXCR4 S338X .…”

Impact of MYD88L265P mutation status on histological transformation of Waldenström Macroglobulinemia

“…The biologic explanation for such an observation is not completely clear at this juncture. The genomic profiles of MYD88 L265P mutated and MYD88 WT WM have considerable overlap, but MYD88 WT WM patients have recently been shown to have additional mutations (TBL1XR1, NFKB2, BCL10, MALT1 genes among others) leading to NF-κB activation, impaired DNA repair and genomic dysregulation which might contribute to increased risk of histological transformation 30,31. Our study comes with the limitations of retrospective analyses,but prospective assessment of an infrequent complication such as transformation in a rare malignancy such as WM is challenging.…”

Clinical and molecular characteristics of lymphoplasmacytic lymphoma not associated with an IgM monoclonal protein: A multicentric study of the Rete Ematologica Lombarda (REL) network

“…We previously described subclonal KMT2D mutations in 24% of WM patients . The KMT2D mutations were described also by the Dana Farber group either among mutant MYD88 , or wild type MYD88 WM patients . The prognostic or predictive impact of these mutations is still unclear.…”