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 MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88L265P 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 MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88L265P is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.
Rodriguez S, Celay J, Goicoechea I, Jimenez C, Botta C, Garcia-Barchino MJ, Garces JJ, Larrayoz M, Santos S, Alignani D, Vilas-Zornoza A, Perez C, Garate S, Sarvide S, Lopez A, Reinhardt HC, Carrasco YR, Sanchez-Garcia I, Larrayoz MJ, Calasanz MJ, Panizo C, Prosper F, Lamo-Espinosa JM, Motta M, Tucci A, Sacco A, Gentile M, Duarte S, Vitoria H, Geraldes C, Paiva A, Puig N, Garcia-Sanz R, Roccaro AM, Fuerte G, San Miguel JF, Martinez-Climent JA, Paiva B