Decoding immune dysregulation in AML: Insights from integrated genomic and transcriptomic analysis.

6519 Background: Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy marked by abnormal proliferation of myeloid progenitor cells, often leading to poor outcomes and high relapse rates. While the genetic underpinnings of AML are well-documented, the role of immune dysregulation in its progression remains underexplored. This study integrates whole exome sequencing (WES) and transcriptome analysis to identify genetic mutations, transcriptional alterations, and immune regulatory disruptions, with a focus on their contributions to hematopoiesis and immune dysfunction. Methods: WES and RNA sequencing were performed on 10 AML patient samples to investigate somatic mutations, differential gene expression, and immune-related pathways. WES data were analyzed to detect mutations in AML-associated genes, while transcriptomic analysis compared gene expression profiles between AML cells and normal hematopoietic stem cells (HSCs). Bioinformatic tools, including differential expression analysis, Gene Set Enrichment Analysis (GSEA), and pathway mapping, were employed to identify key regulatory networks. Single-cell RNA sequencing (scRNA-seq) was conducted to assess cellular heterogeneity and differentiation dynamics, with a focus on immune cell subsets and pathways involved in immune evasion. Results: Analysis revealed recurrent mutations and dysregulation in genes critical to hematopoiesis, apoptosis, and immune regulation, including RUNX1, FLT3, CEBPA, TP53, WT1, GATA2, and TET2 . Transcriptomic profiling highlighted distinct gene expression patterns in AML cells, with significant disruption in cell cycle control, differentiation, and apoptosis. Dysregulated immune pathways, such as IL-7R and PD-1, were identified as key contributors to immune cell activation impairment and immune tolerance. scRNA-seq data provided insights into the cellular heterogeneity of AML, uncovering altered lineage differentiation and immune subset composition, which may facilitate immune evasion and disease progression. Conclusions: This integrative analysis illuminates the interplay between genetic mutations, transcriptional dysregulation, and immune dysfunction in AML. The findings underscore the pivotal role of immune pathways, such as IL-7R and PD-1, in AML pathogenesis, presenting them as potential therapeutic targets. By linking genetic and immune alterations, this study advances our understanding of AML biology and highlights the need for therapies addressing both genetic and immune dysfunctions to improve clinical outcomes.