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

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 Las Rivas, Susana Riesco, Pablo Prieto-Matos, África González-Murillo, Francisco Javier García Criado, María Begoña García Cenador, Manuel Ramírez-Orellana, Belén Andrés, Carolina Vicente-Dueñas (), César Cobaleda (), Kim E. Nichols () and Isidro Sánchez-García ()
Additional contact information
Marta Isidro-Hernández: CSIC-USAL, Campus M. de Unamuno s/n
Ana Casado-García: CSIC-USAL, Campus M. de Unamuno s/n
Ninad Oak: St. Jude Children’s Research Hospital
Silvia Alemán-Arteaga: CSIC-USAL, Campus M. de Unamuno s/n
Belén Ruiz-Corzo: CSIC-USAL, Campus M. de Unamuno s/n
Jorge Martínez-Cano: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas -Universidad Autónoma de Madrid)
Andrea Mayado: Institute of Biomedical Research of Salamanca (IBSAL)
Elena G. Sánchez: Universidad Autónoma de Madrid
Oscar Blanco: Institute of Biomedical Research of Salamanca (IBSAL)
Ma Luisa Gaspar: Carlos III Health Institute
Alberto Orfao: Institute of Biomedical Research of Salamanca (IBSAL)
Diego Alonso-López: Cancer Research Center (CSIC-USAL)
Javier Las Rivas: Institute of Biomedical Research of Salamanca (IBSAL)
Susana Riesco: Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182
Pablo Prieto-Matos: Institute of Biomedical Research of Salamanca (IBSAL)
África González-Murillo: Universidad Autónoma de Madrid
Francisco Javier García Criado: Institute of Biomedical Research of Salamanca (IBSAL)
María Begoña García Cenador: Institute of Biomedical Research of Salamanca (IBSAL)
Manuel Ramírez-Orellana: Universidad Autónoma de Madrid
Belén Andrés: Carlos III Health Institute
Carolina Vicente-Dueñas: Institute of Biomedical Research of Salamanca (IBSAL)
César Cobaleda: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas -Universidad Autónoma de Madrid)
Kim E. Nichols: St. Jude Children’s Research Hospital
Isidro Sánchez-García: CSIC-USAL, Campus M. de Unamuno s/n

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40961-z

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