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

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

doi:10.1038/s41467-023-40961-z

Cited by 5 publications

(1 citation statement)

References 74 publications

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“…As a result, we have learned from mouse models that different immunological stressors are linked to the conversion of preleukemic B cells to B-ALL. Recent experiments involving a murine model have dived deeper into this mechanism of immune stress, indicating that dysregulation of innate immune signaling within preleukemic precursor B cells plays a pivotal role in driving this immune stress, ultimately culminating in leukemia development ( 69 ). Specifically, Myd88 , a central player in immune cell activation via Toll-like receptors (TLRs), undergoes downregulation in immune-stressed pre-malignant cells, and through an inflammation-dependent mechanism, contributes to the onset of leukemia ( 69 ).…”

Section: Mechanisms Of Action Of B-all Risk Factorsmentioning

confidence: 99%

Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia

Casado-García,

Isidro-Hernández,

Alemán-Arteaga

et al. 2023

Front. Immunol.

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B-cell acute lymphoblastic leukemia (B-ALL) stands as the primary contributor to childhood cancer-related mortality on a global scale. The development of the most conventional forms of this disease has been proposed to be conducted by two different steps influenced by different types of risk factors. The first step is led by a genetic insult that is presumably acquired before birth that transforms a healthy cell into a preleukemic one, which is maintained untransformed until the second step takes place. This necessary next step to leukemia development will be triggered by different risk factors to which children are exposed after birth. Murine models that recap the stepwise progression of B-ALL have been instrumental in identifying environmental and genetic factors that contribute to disease risk. Recent evidence from these models has demonstrated that specific environmental risk factors, such as common infections or gut microbiome dysbiosis, induce immune stress, driving the transformation of preleukemic cells, and harboring genetic alterations, into fully transformed leukemic cells. Such models serve as valuable tools for investigating the mechanisms underlying preleukemic events and can aid in the development of preventive approaches for leukemia in child. Here, we discuss the existing knowledge, learned from mouse models, of the impact of genetic and environmental risk factors on childhood B-ALL evolution and how B-ALL prevention could be reached by interfering with preleukemic cells.

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Section: Mechanisms Of Action Of B-all Risk Factorsmentioning

confidence: 99%

Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia

Casado-García,

Isidro-Hernández,

Alemán-Arteaga

et al. 2023

Front. Immunol.

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Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene–Environment Interactions

Cobaleda,

Godley,

Nichols

et al. 2024

Cancer Discovery

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Summary: The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene–environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring. Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.

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Early-life infection depletes preleukemic cells in a mouse model of hyperdiploid B-cell acute lymphoblastic leukemia

Farrokhi,

Atre,

Salitra

et al. 2024

Blood

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Epidemiological studies report opposing influences of infection on childhood B cell acute lymphoblastic leukemia (B-ALL). Although infections in the first year of life appear to exert the largest impact on leukemia risk, the effect of early pathogen exposure on the fetal preleukemia cells (PLC) that lead to B-ALL has yet to be reported. Using cytomegalovirus as a model early-life infection, we show that virus exposure within one week of birth induces profound depletion of transplanted B-ALL cells in two mouse models and of in situ-generated PLC in Eu-ret mice. The age-dependent depletion of PLC results from an elevated STAT4-mediated cytokine response in neonates, with high levels of IL-12p40-driven IFN-g production inducing PLC death. Similar PLC depletion can be achieved in adult mice by impairing viral clearance. These findings provide mechanistic support for an inhibitory effect of early-life infection on B-ALL progression and could inform development of therapeutic or preventative approaches.

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

Cited by 5 publications

References 74 publications

Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia

Lessons from mouse models in the impact of risk factors on the genesis of childhood B-cell leukemia

Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene–Environment Interactions

Early-life infection depletes preleukemic cells in a mouse model of hyperdiploid B-cell acute lymphoblastic leukemia

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