Associations of rs55829688 and rs145204276 Promoter Variants with lncRNA GAS5 Expression in AML: Prognostic Significance and Functional Analysis

<b>Background/Objectives</b>: Acute myeloid leukemia is a genetically diverse hematological malignancy where patient outcomes vary significantly. Long non-coding RNA (lncRNA) <i>GAS5</i> acts as a tumor suppressor and is frequently downregulated in various cancers, as well as in AML. In the current study, we aimed to explore the effects of GAS5 promoter variants on its expression levels in AML patients, their prognostic significance, and to investigate their functional effects. <b>Methods</b>: The <i>GAS5</i> promoter region containing rs55829688 and rs145204276 was sequenced in 75 AML patients. Statistical analyses were performed to assess their associations with <i>GAS5</i> expression and outcomes. An in vitro functional study in K562 cells evaluated the effects of these variants on the transcriptional activity of constructs containing each variant. In silico analysis was used to predict changes to transcription factor binding sites. <b>Results</b>: Patients carrying the rs55829688 TC/CC genotype exhibited lower <i>GAS5</i> expression and were more frequently categorized into the adverse risk group. In intermediate-risk patients, this genotype trended toward lower overall survival and higher bone marrow blast percentages. In vitro, the construct harboring the rs55829688 C allele showed a two-fold decrease in reporter gene activity compared to the construct bearing both wild type alleles. In silico analysis identified RUNX3 as the most likely transcription factor affected by this variant. The variant rs145204276 was considered for the first time in AML; however, no significant clinical associations or transcriptional effects were found. <b>Conclusions</b>: Taken together, our findings provide evidence that the rs55829688 promoter variant reduces <i>GAS5</i> expression in AML and could potentially be a prognostic marker.