A multiomic analysis of Waldenström macroglobulinemia defines distinct disease subtypes.

We carried out a single-cell multiomic analysis on a series of MYD88-mutated Waldenström macroglobulinemia (WM) patients and identified 2 distinct subtypes of disease, memory B-cell (MBC)-like and plasma cell (PC)-like, based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully toward a PC and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the MBC stage, upregulates key MBC genes, and is characterized by upregulated B-cell receptor and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling. In contrast, the PC-like subtype can partially differentiate toward a PC, upregulates key PC genes, has enhanced NF-κB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin with sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the 2 disease subtypes were validated further using hierarchical clustering of bulk RNA-sequencing data from a secondary set of patients. The biological significance of the subtypes was further established using whole-genome sequencing, in which it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype, and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as 2 disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features, with potential implications for WM treatment strategies.