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 longst...

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Detalles Bibliográficos
Autores: Isidro-Hernández, Marta, Casado-García, Ana, Oak, Ninad, Alemán-Arteaga, Silvia, Ruiz-Corzo, Belén, Martínez-Cano, Jorge, Mayado, Andrea, Sánchez, Elena G, Blanco, Oscar, Gaspar, Maria Luisa, Orfao, Alberto, Alonso-López, Diego, De Las Rivas, Javier, Riesco, Susana, Prieto-Matos, Pablo, González-Murillo, África, García-Criado, Francisco Javier, García-Cenador, María Begoña, Ramírez-Orellana, Manuel, Andres, Belen de, Vicente-Dueñas, Carolina, Cobaleda, César, Nichols, Kim E, Sánchez-García, Isidro
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/16839
Acceso en línea:http://hdl.handle.net/20.500.12105/16839
Access Level:acceso abierto
Palabra clave:Burkitt Lymphoma
Leukemia
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Animals
Mice
Precursor Cells, B-Lymphoid
Myeloid Differentiation Factor 88
Signal Transduction
Adaptor Proteins, Signal Transducing
Immunity, Innate
Descripción
Sumario: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.

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