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Updated: Dec 2, 2025
In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells
Published on: January 20, 2019
Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis
Marta Isidro-Hernández1,2, Andrea Mayado2,3, Ana Casado-García1,2
1Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Campus M. de Unamuno s/n, Salamanca, Spain.
Insights
Children with inherited PAX5 mutations are at higher risk for B-cell acute lymphoblastic leukemia (B-ALL). Infections enhance interleukin-6 (IL-6) production, promoting leukemia growth, and IL-6 inhibition offers a therapeutic strategy for PAX5-mutant B-ALL.
Area of Science:
- Hematology
- Oncology
- Immunology
Background:
- PAX5 mutations are common in B-cell acute lymphoblastic leukemia (B-ALL), increasing disease risk.
- Altered inflammatory markers in newborns are linked to later B-ALL development.
- The role of inflammation in B-ALL pathogenesis remains unclear.
Purpose of the Study:
- To investigate the link between PAX5 mutations, inflammation, and B-ALL development.
- To explore the role of interleukin-6 (IL-6) in Pax5-dependent B-ALL.
- To evaluate IL-6 as a therapeutic target in B-ALL.
Main Methods:
- Studied Pax5 heterozygous mice, assessing IL-6 production during infection.
- Utilized genetic downregulation and pharmacologic inhibition of IL-6 in mouse models.
- Validated findings in human B-ALL samples.
Main Results:
- Pax5 heterozygosis combined with infection enhances IL-6 production, promoting leukemia growth via autocrine signaling.
- Genetic and pharmacologic IL-6 inhibition significantly retarded B-ALL progression in mice.
- IL-6 signaling was confirmed as a critical factor in human PAX5-mutant B-ALL.
Conclusions:
- Aberrant IL-6 expression due to PAX5 loss is a key feature of Pax5-dependent B-ALL.
- IL-6 represents a significant therapeutic vulnerability in PAX5-mutant B-ALL.
- Targeting IL-6 may offer a novel treatment strategy for B-ALL.
Abstract:
PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers have been detected in neonatal blood spot samples of children who later developed B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 heterozygosis, in the presence of infections, results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. Furthermore, in vivo genetic downregulation of IL-6 in these Pax5 heterozygous mice retards B-cell leukemogenesis, and in vivo pharmacologic inhibition of IL-6 with a neutralizing antibody in Pax5 mutant mice with B-ALL clears leukemic cells. Additionally, this novel IL-6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.
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