Acute leukemias are highly aggressive hematologic malignancies that demand intensive chemotherapy regimens. However, drug toxicity remains a major barrier to treatment success and patient survival. In this context, pharmacogenomics offers a promising strategy by identifying single-nucleotide variants (SNVs) that influence drug metabolism, efficacy, and toxicity, ultimately impacting treatment outcomes. This study analyzed data from the ClinPGx/PharmGKB database to identify clinically annotated variants related to chemotherapy response in Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). A total of 24 variants were curated for AML and 57 for ALL. Among these, nonsynonymous variants were most frequent in ALL (31.6%), while synonymous variants predominated in AML (33.3%). Although traditionally considered neutral, synonymous and intronic variants may influence gene expression through regulatory or splicing mechanisms. The analysis revealed clinically significant variants associated with chemotherapy response, particularly in the ABCB1 gene, observed in 12.5% of AML and 10.5% of ALL cases. Several variants, particularly TPMT, NUDT15, ABCC1, SLC28A3, and RARG, were associated with severe adverse effects such as myelotoxicity, mucositis, cardiotoxicity, and hepatotoxicity. This study reinforces the importance of genetic variants in modulating the therapeutic response and toxicity to chemotherapy drugs in acute leukemias. Analysis of ClinPGx/PharmGKB data emphasizes ABCB1 as a potential resistance marker and supports pre-treatment genotyping of genes like TPMT and NUDT15 to prevent severe toxicities. Future advances should include the expansion of pharmacogenetic studies in underrepresented populations and the clinical validation of new markers in prospective trials, aiming to consolidate precision medicine as a routine part of the therapeutic management of acute leukemias.

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.

Background/Objectives: Multiple myeloma (MM) is a genetically complex hematological neoplasm driven by accumulating genomic events. Despite therapeutic advances, MM remains an incurable disease with a complex molecular picture. Characterizing copy number alterations (CNAs) represents a promising strategy to identify dysregulated biological pathways and reveal novel therapeutic targets. This study aimed to characterize the CNA profile across pre-malignant gammopathies, MM, and plasma cell leukemia, identifying the key molecular pathways involved in disease progression. Methods: Genomic analysis via array comparative genomic hybridization (aCGH) was performed on bone marrow samples from 21 patients representing all disease stages. Data were analyzed in CytoGenomics software version 5.3.0.14 utilizing the GRCh38/hg38 human genome. CNAs were identified with the ADM-2 algorithm, followed by functional enrichment analysis to determine significantly overrepresented pathways. Results: Pre-malignant evaluation suggested a potential functional switch from innate immunity and olfactory signaling in Monoclonal Gammopathy of Undetermined Significance (MGUS) to DNA repair mechanisms in Smoldering Multiple Myeloma (SMM), marking early genomic instability. In active MM, 280 CNAs were detected. Low-risk (ISS-I) patients retained cell adhesion signatures, whereas high-risk (ISS-III) profiles exhibited extensive genomic instability affecting tissue remodeling and cytokine signaling. Conclusions: In summary, our descriptive findings suggest that early alterations in immune response and olfactory signaling pathways may emerge as potential triggers driving pre-malignant dyscrasias and active MM development.