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Decreased IL-10 accelerates B-cell leukemia/lymphoma in a mouse model of pediatric lymphoid leukemia
Briana A Fitch1, Mi Zhou1, Jamilla Situ1
1Department of Laboratory Medicine.
Insights
Low interleukin-10 (IL-10) levels increase the risk of pediatric B-cell acute lymphoblastic leukemia (B-ALL) by impairing B-cell development and increasing DNA damage. Antibiotics reduced these preleukemic defects in mice.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Childhood infections and inflammation influence B-cell acute lymphoblastic leukemia (B-ALL) risk.
- Neonatal inflammatory markers are linked to B-ALL risk through unknown mechanisms.
Purpose of the Study:
- To investigate the role of interleukin-10 (IL-10) deficiency in pediatric B-ALL pathogenesis.
- To elucidate the mechanisms by which low IL-10 impacts B-cell development and DNA damage.
Main Methods:
- Utilized preleukemic Cdkn2a-/-Il10-/- mice to model IL-10 deficiency.
- Administered antibiotics to assess the impact on inflammation and B-cell defects.
- Employed an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- mouse model to study B-ALL acceleration and mutational profiles.
Main Results:
- IL-10 deficiency impaired B lymphopoiesis and increased B-cell DNA damage, associated with specific proinflammatory cytokines.
- Antibiotic treatment attenuated inflammation and B-cell defects in preleukemic mice.
- Reduced IL-10 levels accelerated B-ALL development in a dose-dependent manner and altered tumor mutational profiles in mice.
Conclusions:
- Low IL-10 levels create a risk for leukemic transformation by affecting B-cell development and DNA integrity.
- Findings support the hypothesis that microbial dysbiosis contributes to pediatric B-ALL development.
- This research illuminates a potential mechanism linking inflammation, IL-10, and B-ALL risk.
Abstract:
Exposures to a wide repertoire of common childhood infections and strong inflammatory responses to those infections are associated with the risk of pediatric B-cell acute lymphoblastic leukemia (B-ALL) in opposing directions. Neonatal inflammatory markers are also related to risk by unknown mechanism(s). Here, we demonstrate that interleukin-10 (IL-10) deficiency, which is associated with childhood B-ALL, indirectly impairs B lymphopoiesis and increases B-cell DNA damage in association with a module of 6 proinflammatory/myeloid-associated cytokines (IL-1α, IL-6, IL-12p40, IL-13, macrophage inflammatory protein-1β/CCL4, and granulocyte colony-stimulating factor). Importantly, antibiotics attenuated inflammation and B-cell defects in preleukemic Cdkn2a-/-Il10-/- mice. In an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- mouse model of B-ALL, decreased levels of IL-10 accelerated B-cell neoplasms in a dose-dependent manner and altered the mutational profile of these neoplasms. Our results illuminate a mechanism through which a low level of IL-10 can create a risk for leukemic transformation and support developing evidence that microbial dysbiosis contributes to pediatric B-ALL.
