Integrated Genomic and Transcriptomic Profiling of Isolated Trisomies in AML Reveals Cell Cycle Dysregulation and...

Acute myeloid leukaemia (AML) with isolated trisomies (ITs) represents a distinct cytogenetic subgroup with heterogeneous clinical behaviour and incompletely defined molecular features. To explore its genomic and transcriptomic landscape, we performed next-generation sequencing (NGS) on 14 AML patients harbouring isolated trisomies of chromosomes 8, 9, 10, 13, 14, 21 and 22. RNA sequencing (RNA-Seq) was conducted on 15 samples, including 12 with IT and 3 cytogenetically normal AML cases (normal karyotype, NK-AML) serving as controls. Trisomy 8 was most frequent, followed by chromosomes 13, 14 and 21. Recurrent mutations were identified in epigenetic regulators (DNMT3A, IDH1/2, ASXL1, TET2). Transcriptomic profiling stratified cases into IT-8, IT-21 and IT-13+22 subgroups. Gene set enrichment analysis (GSEA) revealed shared downregulation of cell cycle-related pathways (e.g., G2M checkpoint) and subgroup-specific patterns: oxidative stress and unfolded protein response in IT-8; epithelial-mesenchymal transition and oxidative phosphorylation in IT-21; inflammatory signalling (IL-6/JAK/STAT, TNF-α/NF-κB) in IT-13+22. A core set of 60 differentially expressed genes (DEGs) was shared, with nine hub genes related to cell cycle (MCM4, CDC7, CDC25A, DHFR), proteostasis (HSPA5, DNAJC3, CALR, HSP90B1) and inflammation. Drug sensitivity profiling revealed subgroup-specific vulnerabilities: IT-8 to DNA damage checkpoint inhibitors, IT-21 to PLK/mTOR inhibitors and IT-13+22 to BRAF/EGFR-targeted agents. These findings highlight AML-IT heterogeneity and therapeutic potential.