Isidro-Hernández, MartaCasado-García, AnaOak, NinadAlemán-Arteaga, SilviaRuiz-Corzo, BelénMartínez-Cano, JorgeMayado, AndreaSánchez, Elena GBlanco, OscarGaspar, Maria LuisaOrfao, AlbertoAlonso-López, DiegoDe Las Rivas, JavierRiesco, SusanaPrieto-Matos, PabloGonzález-Murillo, ÁfricaGarcía-Criado, Francisco JavierGarcía-Cenador, María BegoñaRamírez-Orellana, ManuelAndres, Belen deVicente-Dueñas, CarolinaCobaleda, CésarNichols, Kim ESánchez-García, Isidro2023-12-182023-12-182023-08-24Nat Commun. 2023 Aug 24;14(1):5159.http://hdl.handle.net/20.500.12105/16839The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5+/- B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5+/-Myd88+/- mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5+/- mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.engVoRBurkitt LymphomaLeukemiaPrecursor B-Cell Lymphoblastic Leukemia-LymphomaAnimalsMicePrecursor Cells, B-LymphoidMyeloid Differentiation Factor 88Signal TransductionAdaptor Proteins, Signal TransducingImmunity, InnateAtribución 4.0 Internacional37620322141515910.1038/s41467-023-40961-z2041-1723Nature communicationsopen access