Elucidating the Role of Estrogen Effects in Leukemia: Insights from Single-Cell RNA Sequencing and Mendelian Randomization

<b>Background:</b> Epidemiological studies have confirmed the potential role of estrogen effects in influencing the development and outcome of leukemia. Estrogen effects are increasingly attracting research interest for their potential antitumor effects beyond gynecological tumors. However, their causal relationship remains unclear. <b>Methods</b>: In a novel approach, this study integrates single-cell RNA sequencing (scRNA-seq) with Mendelian randomization (MR) to explore the relationship between estrogen (and its receptor) and leukemia (and its related proteins). This integration showcases the uniqueness of our methodology and provides a new perspective for understanding the molecular relationship between them. Secondary analyses using genetic risk scores (GRS) were performed to further verify the robustness of the results. <b>Results</b>: Our scRNA-seq analysis identified 14 BMMC mononuclear cell subsets, and the result showed that the estrogen receptor was implicated in leukemia. The MR results showed that there was a relationship between estradiol and leukemia inhibitory factor (β = 0.0621; <i>P</i> = 0.0229), and leukemia inhibitory factor receptor (β = 0.0665; <i>P</i> = 0.0218). The result of GRS analysis verified the MR analysis. <b>Conclusions:</b> While both scRNA-seq and MR have yielded intriguing results, inconsistencies between these methodologies hint at a more elaborate underlying mechanism. The observed discrepancies underscore the complexity of the estrogen effects-leukemia relationship, suggesting that elucidating these interactions demands larger cohorts and enhanced sequencing depth in future studies. This research paves the way for a more nuanced understanding of the role of estrogen effects in leukemia and sets the stage for targeted therapeutic interventions.