Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice.

The 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. © 2023. Springer Nature Limited.

Citation

Marta Isidro-Hernández, Ana Casado-García, Ninad Oak, Silvia Alemán-Arteaga, Belén Ruiz-Corzo, Jorge Martínez-Cano, Andrea Mayado, Elena G Sánchez, Oscar Blanco, Ma Luisa Gaspar, Alberto Orfao, Diego Alonso-López, Javier De Las Rivas, Susana Riesco, Pablo Prieto-Matos, África González-Murillo, Francisco Javier García Criado, María Begoña García Cenador, Manuel Ramírez-Orellana, Belén de Andrés, Carolina Vicente-Dueñas, César Cobaleda, Kim E Nichols, Isidro Sánchez-García. Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice. Nature communications. 2023 Aug 24;14(1):5159

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PMID: 37620322

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