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

Author

Listed:
  • Marta Isidro-Hernández

    (CSIC-USAL, Campus M. de Unamuno s/n
    Institute of Biomedical Research of Salamanca (IBSAL))

  • Ana Casado-García

    (CSIC-USAL, Campus M. de Unamuno s/n
    Institute of Biomedical Research of Salamanca (IBSAL))

  • Ninad Oak

    (St. Jude Children’s Research Hospital)

  • Silvia Alemán-Arteaga

    (CSIC-USAL, Campus M. de Unamuno s/n
    Institute of Biomedical Research of Salamanca (IBSAL))

  • Belén Ruiz-Corzo

    (CSIC-USAL, Campus M. de Unamuno s/n
    Institute of Biomedical Research of Salamanca (IBSAL))

  • 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)
    CSIC/Universidad de Salamanca)

  • Elena G. Sánchez

    (Universidad Autónoma de Madrid)

  • Oscar Blanco

    (Institute of Biomedical Research of Salamanca (IBSAL)
    Universidad de Salamanca)

  • Ma Luisa Gaspar

    (Carlos III Health Institute)

  • Alberto Orfao

    (Institute of Biomedical Research of Salamanca (IBSAL)
    CSIC/Universidad de Salamanca)

  • Diego Alonso-López

    (Cancer Research Center (CSIC-USAL))

  • Javier Las Rivas

    (Institute of Biomedical Research of Salamanca (IBSAL)
    Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL))

  • Susana Riesco

    (Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182)

  • Pablo Prieto-Matos

    (Institute of Biomedical Research of Salamanca (IBSAL)
    Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182)

  • África González-Murillo

    (Universidad Autónoma de Madrid)

  • Francisco Javier García Criado

    (Institute of Biomedical Research of Salamanca (IBSAL)
    , Universidad de Salamanca)

  • María Begoña García Cenador

    (Institute of Biomedical Research of Salamanca (IBSAL)
    , Universidad de Salamanca)

  • Manuel Ramírez-Orellana

    (Universidad Autónoma de Madrid)

  • Belén Andrés

    (Carlos III Health Institute)

  • Carolina Vicente-Dueñas

    (Institute of Biomedical Research of Salamanca (IBSAL)
    Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182)

  • 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
    Institute of Biomedical Research of Salamanca (IBSAL))

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.

Suggested 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 Or, 2023. "Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40961-z
    DOI: 10.1038/s41467-023-40961-z
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    References listed on IDEAS

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    1. Daniel C. Jeffares & Clemency Jolly & Mimoza Hoti & Doug Speed & Liam Shaw & Charalampos Rallis & Francois Balloux & Christophe Dessimoz & Jürg Bähler & Fritz J. Sedlazeck, 2017. "Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast," Nature Communications, Nature, vol. 8(1), pages 1-11, April.
    2. César Cobaleda & Wolfram Jochum & Meinrad Busslinger, 2007. "Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors," Nature, Nature, vol. 449(7161), pages 473-477, September.
    3. Guillermo Rodríguez-Hernández & Friederike V. Opitz & Pilar Delgado & Carolin Walter & Ángel F. Álvarez-Prado & Inés González-Herrero & Franziska Auer & Ute Fischer & Stefan Janssen & Christoph Barten, 2019. "Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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