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

• Published in: Nature communications Vol. 14; no. 1; p. 5159
• Main Authors: 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, Ma Luisa, Orfao, Alberto, Alonso-López, Diego, De Las Rivas, Javier, Riesco, Susana, Prieto-Matos, Pablo, González-Murillo, África, Criado, Francisco Javier García, Cenador, María Begoña García, Ramírez-Orellana, Manuel, de Andrés, Belén, Vicente-Dueñas, Carolina, Cobaleda, César, Nichols, Kim E., Sánchez-García, Isidro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.08.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/1; 38/23; 38/61; 38/77; 38/90; 631/67/1990/283/2125; 692/4028/67/1990/283/2125; Acute lymphoblastic leukemia; Adaptor Proteins, Signal Transducing; Animal models; Animals; Burkitt Lymphoma; Down-regulation; Genetic transformation; Humanities and Social Sciences; Immunity; Immunity, Innate; Immunology; Innate immunity; Leukemia; Lymphatic leukemia; Lymphocytes B; Mice; multidisciplinary; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Pax5 protein; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cells, B-Lymphoid; Precursors; Science; Science (multidisciplinary); Signal Transduction; Therapeutic targets; TLR3 protein; Toll-like receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40961-z

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. Immunological stressors are linked to the transformation of preleukemic B cells to B-cell acute lymphoblastic leukemia. Here the authors show a dysregulation of innate immune signaling in preleukemic precursor B cells and link to the development of B-cell acute lymphoblastic leukemia in a murine model.