Preneoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma
Menée à l'aide de modèles murins transgéniques et d'échantillons de moelle osseuse prélevés chez des personnes âgées et des patients atteints d'un lymphome lymphoplasmocytaire, cette étude démontre que la survenue de la mutation L265P au niveau du gène MYD88 est un événement qui précède la lymphomagenèse
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.
Science Advances 2022