Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma
Keywords: 
Lymphoplasmacytic lymphoma
Mutations
MYD88
Issue Date: 
2022
ISSN: 
2375-2548
Note: 
Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Citation: 
Rodríguez-Díaz, S. (Saray); Celay-Leoz, I. (Ion); Goicoechea-Oroz, I. (Ibai); et al. "Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma". Science Advances. 8 (3), 2022, eabl4644
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, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.

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