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Bioinformatics-driven dissection of PANoptosis-related molecular subtypes and tumor immune microenvironment
Wen-Ting Pei1, Chun-Lei Liu2, Xiao-Ling Li3
1Department of Pediatrics, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), No. 23976 Jingshi Road, Huaiyin District, Jinan, 250000, Shandong Province, China.
Abstract:
PANoptosis, an integrated programmed cell death modality encompassing apoptosis, necroptosis, and pyroptosis, exerts pleiotropic effects on tumor immune surveillance and immune escape. However, the molecular mechanisms underlying PANoptosis in pediatric acute myeloid leukemia (AML) remain poorly elucidated. Here, we performed bioinformatic analyses of AML bone marrow transcriptomic data from the TARGET database, aiming to define PANoptosis-associated molecular subtypes, characterize tumor immune microenvironment (TIME) heterogeneity, and identify candidate regulatory genes and small-molecule binders. We identified 68 PANoptosis-related genes and used unsupervised clustering to resolve four molecular subtypes (C1-C4) with distinct clinical outcomes and TIME profiles. The C2 subtype exhibited robust CD8⁺ cytotoxic T-cell and natural killer (NK) cell activity linked to favorable prognosis, whereas the C1 subtype displayed immune suppression and poor survival. We identified an IGF1-CCL2-CCL4 gene set correlated with PANoptosis regulation and enriched in Toll-like receptor signaling. In silico molecular docking suggested SB216763 as a candidate ligand for these targets, though this requires experimental validation. Our findings outline PANoptosis-associated heterogeneity in pediatric AML and provide a stratification framework for future mechanistic and translational studies.
Insights
This study defines PANoptosis subtypes in pediatric acute myeloid leukemia (AML), revealing distinct immune microenvironments and patient outcomes. Findings identify potential therapeutic targets for AML treatment.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- PANoptosis, a programmed cell death pathway, influences tumor immunity but its role in pediatric acute myeloid leukemia (AML) is unclear.
- Understanding PANoptosis mechanisms is crucial for developing novel pediatric AML therapies.
Purpose of the Study:
- To define PANoptosis-associated molecular subtypes in pediatric AML.
- To characterize tumor immune microenvironment (TIME) heterogeneity.
- To identify potential regulatory genes and small-molecule drug targets.
Main Methods:
- Bioinformatic analysis of pediatric AML bone marrow transcriptomic data (TARGET database).
- Unsupervised clustering to identify molecular subtypes based on 68 PANoptosis-related genes.
- In silico molecular docking for drug target identification.
Main Results:
- Four distinct PANoptosis-associated molecular subtypes (C1-C4) were identified.
- Subtype C2 showed high CD8+ T-cell and NK cell activity, correlating with better prognosis.
- Subtype C1 exhibited immune suppression and poor survival.
- An IGF1-CCL2-CCL4 gene set linked to PANoptosis and Toll-like receptor signaling was identified.
Conclusions:
- PANoptosis contributes to significant molecular and immune heterogeneity in pediatric AML.
- Identified subtypes offer a framework for stratifying patients for targeted therapies.
- Further research and experimental validation are needed for identified gene sets and drug candidates.
