IL-12 abrogates calcineurin-dependent immune evasion during leukemia progression
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ABSTRACT:
PROVIDER: PRJNA534497 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8950560.fastq.gz | Fastqsanger.gz | |||
| SRR8950561.fastq.gz | Fastqsanger.gz | |||
| SRR8950562.fastq.gz | Fastqsanger.gz | |||
| SRR8950563.fastq.gz | Fastqsanger.gz | |||
| SRR8950564.fastq.gz | Fastqsanger.gz |
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Project description:Exploitation of the immune system has emerged as an important therapeutic strategy for acute lymphoblastic leukemia (ALL). However, the mechanisms of immune evasion during leukemia progression remain poorly understood. We sought to understand the role of calcineurin in ALL and observed that knocking-down calcineurin B (CnB) in leukemia cells dramatically prolonged survival in immune-competent but not immune-deficient recipients. Furthermore, immune-competent recipients were protected from challenge with leukemia if they were first immunized with CnB-deficient leukemia, suggesting robust adaptive immunity. In the bone marrow, recipients of CnB-deficient leukemia had expansion of T cell populations as compared to controls. Gene expression analyses of leukemia cells extracted from bone marrow identified Cn-dependent significant changes in the expression of immuno-regulatory genes. We confirmed increased secretion of IL-12 from CnB-deficient leukemia cells, sufficient to induce T cell activation ex vivo, an effect that was abolished when IL-12 was neutralized. Strikingly, recombinant IL-12 prolonged survival of mice challenged with highly aggressive B-ALL. Moreover, gene expression analyses from children with ALL demonstrate prolonged survival in those with higher expression of either IL-12A or IL-12B. These data suggest that leukemia cells are dependent upon calcineurin for immune evasion by restricting the regulation of pro-inflammatory genes, particularly IL-12.
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Project description:Exploitation of the immune system has emerged as an important therapeutic strategy for acute lymphoblastic leukemia (ALL). However, the mechanisms of immune evasion during leukemia progression remain poorly understood. We sought to understand the role of calcineurin in ALL and observed that depletion of calcineurin B (CnB) in leukemia cells dramatically prolongs survival in immune-competent but not immune-deficient recipients. Immune-competent recipients were protected from challenge with leukemia if they were first immunized with CnB-deficient leukemia, suggesting robust adaptive immunity. In the bone marrow (BM), recipients of CnB-deficient leukemia harbored expanded T-cell populations as compared with controls. Gene expression analyses of leukemia cells extracted from the BM identified Cn-dependent significant changes in the expression of immunoregulatory genes. Increased secretion of IL12 from CnB-deficient leukemia cells was sufficient to induce T-cell activation ex vivo, an effect that was abolished when IL12 was neutralized. Strikingly, recombinant IL12 prolonged survival of mice challenged with highly aggressive B-ALL. Moreover, gene expression analyses from children with ALL showed that patients with higher expression of either IL12A or IL12B exhibited prolonged survival. These data suggest that leukemia cells are dependent upon calcineurin for immune evasion by restricting the regulation of proinflammatory genes, particularly IL12. SIGNIFICANCE: This report implicates calcineurin as an intracellular signaling molecule responsible for immune evasion during leukemia progression and raises the prospect of re-examining IL12 as a therapeutic in leukemia.
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