Preneoplastic somatic mutations including <i>MYD88</i> <sup>L265P</sup> in lymphoplasmacytic lymphoma
Sara Rodríguez, Jon Celay, Ibai Goicoechea, Cristina Jiménez, Cirino Botta, María J. García‐Barchino, Juan‐José Garcés, Marta Larráyoz, Susana Santos, Diego Alignani, Amaia Vilas‐Zornoza, Cristina Pérez, Sonia Gárate, Sarai Sarvide, Aitziber López, Hans-Christian Reinhardt, Yolanda R. Carrasco, Isidro Sánchez-Garcı́a, María José Larráyoz, Marı́a José Calasanz, Carlos Panizo, Felipe Prósper, José María Lamo-Espinosa, Marina Motta, Alessandra Tucci, Antonio Sacco, Massimo Gentile, Sara Duarte, Helena Vitória, Catarina Geraldes, Artur Paiva, Noemí Puig, Ramón García‐Sánz, Aldo M. Roccaro, Gema Fuerte, Jesús F. San Miguel, José A. Martinez‐Climent, Bruno Paiva
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.