1. Preneoplastic somatic mutations including MYD88 L265P in lymphoplasmacytic lymphoma.
- Author
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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, and Paiva B
- Subjects
- Aged, Animals, Humans, Mice, Mutation, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism, Lymphoma, Lymphoma, B-Cell metabolism, Waldenstrom Macroglobulinemia diagnosis, Waldenstrom Macroglobulinemia genetics, Waldenstrom Macroglobulinemia pathology
- Abstract
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 MYD88
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 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.- Published
- 2022
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