MYD88 L265P somatic mutation in Waldenstrom’s Macroglobulinemia

Background: Waldenstrom’s Macroglobulinemia (WM) is an incurable, IgM secreting lymphoplasmacytic lymphoma (LPL) with overlapping clinicopathological features to IgM secreting monoclonal gammopathy of unknown significance (MGUS), marginal zone lymphoma (MZL) and myeloma (MM). The underlying mutation for WM remains to be delineated. Methods: Whole genome sequencing (WGS) of bone marrow (BM) LPL cells was performed for 30 WM patients and included sequencing of paired normal/tumor tissues for 10 patients. Sanger sequencing was used to validate these findings in samples from an expanded cohort of patients with LPL, other overlapping B-cell disorders, and healthy donors. Results: A somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in all 10 paired, and 17/20 unpaired WM patients which predicted for an amino acid change (L265) in MYD88, a mutation which triggers IRAK/MAPK/NF-κβ signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49/54 WM and 3/3 non-IgM secreting LPL patients (91.2% of all LPL patients). MYD88 L265P was absent in normal paired tissues from WM/LPL patients, healthy donor B-cells, and absent or rarely expressed in samples from MM, MZL or IgM MGUS patients. Mutations in ARID1A (5/30; 17%) leading to premature stop or frameshift were also identified, which associated with greater disease burden. Lastly, 2 of 3 WM patients with wild type MYD88 had variants in MLL2. Conclusions: MYD88 L265P is a highly recurring mutation in WM/LPL patients, which can aid in differentiating WM/LPL from overlapping B-cell disorders, and provides a novel target for the development of therapeutics for WM/LPL.