Preneoplastic somatic mutations including <i>MYD88</i> ^L265P in lymphoplasmacytic lymphoma

Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated <i>MYD88</i>. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found <i>MYD88</i>^L265P in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated <i>MYD88</i> in B cell precursors and <i>BCL2</i> overexpression. Thus, <i>MYD88</i>^L265P is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.