Transcriptomic Profiling of Pim Kinases in Acute Leukemia Highlights Pim3 Upregulation and Its Association with Cytogenetic Risk and Stress Response Pathways

Background/Objectives: The PIM kinase family, comprising three serine/threonine kinase isoforms (PIM1, PIM2, and PIM3), plays a fundamental role in various cancer types, where they are frequently described as regulators of proliferation, survival, and metabolic pathways. Acute leukemia is a group of hematological malignancies characterized by the uncontrolled clonal proliferation of hematopoietic stem cells, encompassing myeloid (AML) and lymphoblastic (ALL) lineages, which together present limited therapeutic options and poor clinical outcomes. This study investigated the correlation between PIM kinase signaling pathways and the clinicopathological features, molecular pathway interactions, and cytogenetic risk stratification of patients with acute leukemia. Methods: Microarray data and clinical information from AML and ALL patients were retrieved from the Gene Expression Omnibus database. The expression levels of PIM1, PIM2, and PIM3 were assessed across leukemia subtypes and cytogenetic risk groups using ANOVA or Kruskal–Wallis tests, with Bonferroni post hoc correction, performed in R (v4.5.1). A transcriptome-wide co-expression analysis was conducted using Spearman’s rank correlation to identify genes correlated with each PIM isoform. Subsequently, Gene Set Enrichment Analysis (GSEA) was performed on pre-ranked gene lists using the clusterProfiler (v4.16.0) package and Hallmarks of Cancer gene signatures, with pathway significance determined by Benjamini–Hochberg-adjusted FDR < 0.05. Results: Transcriptomic analysis revealed distinct expression patterns of the PIM kinase family between AML and ALL subtypes, identifying PIM3 as the predominantly dysregulated isoform, marked by significant overexpression across both lineages. Risk-stratified analysis further demonstrated that PIM expression is highly context-dependent, exhibiting dynamic variation across cytogenetic risk groups. Functional enrichment analysis highlighted a potential functional redundancy and compensatory mechanisms among PIM isoforms, with enriched pathways predominantly associated with stress tolerance, hypoxia adaptation, and inflammatory signaling, rather than classical proliferative signatures. Conclusions: Collectively, these findings position the PIM kinase family as a dynamically regulated axis in acute leukemia, deeply integrated with cytogenetic risk profiles and stress-adaptation mechanisms. The consistent upregulation of PIM3 and its correlation with inflammatory and hypoxic signatures suggest a potential role in facilitating tumor survival within adverse microenvironments.