The Evolution and Subtypes of Waldenstrom Macroglobulinemia: Findings from a Multi-omic Analysis of 249 Treatment Naive MYD88L265P Mutated Patients.

To study the heterogeneity of transcriptional and genomic traits that underlie the clinical presentation of untreated Waldenstrom’s Macroglobulinemia (WM), we performed multi-omic studies in 249 treatment-naive patients with WM. For all patients, RNASeq was performed on CD19-selected bone marrow (BM) MYD88 mutated samples as well as 13 paired CD19 ⁺ CD27 ⁻ and CD19 ⁺ CD27 ⁺ peripheral blood samples from healthy donors. Whole exome sequencing (WES) was also analyzed on paired tumor and germline DNA for 229 of these patients and DNA methylation status was assessed by enhanced reduced representational bisulfite sequencing (ERRBS) for 32 samples. The ERRBS and transcriptional data identified two distinct cells of origin for WM leading to two independent WM subtypes known as B-cell Like (BCL) and Plasma Cell Like (PCL). A third subtype, Early WM, was observed primarily in smoldering WM and was present in both ERRBS clusters identifying it as a transcriptional state common to early BCL and PCL. We further identified the WM Evolutionary Score (EScore), a gene signature common to all samples that predicted time to first therapy and corresponded with progression to symptomatic WM. Analysis of the EScore revealed a subclone expressing pre-B-cell, T-cell, stem cell and myeloid markers that was confirmed by flow cytometry and detected in early (smoldering) WM with subpopulations persisting with WM evolution. Our findings have important implications for WM pathogenesis. The evolution from the Early WM subtype to either BCL or PCL and EScore explains much of the genomic, transcriptional and clinical heterogeneity of WM including clinical outcomes to primary therapy.