Association between Lipid Profile and Molecular Signature of Monocytes in Patients with Lower-Risk MDS

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with accelerated atherosclerosis and a 40% increased risk of cardiovascular disease (CVD), linked to increased innate immune cell activation (Jaiswal et al., 2017). Monocytes are critical players in CVD, due to their infiltration in atherosclerotic plaques and their differentiation to foam cells, whereas dyslipidemia is linked to long-term inflammatory activity of monocytes (Mitroulis et al., 2023). Herein, we sought to investigate whether lipid profile is associated with the molecular signature of peripheral monocytes in patients with lower-risk MDS (LR-MDS; i.e., IPSS-R <3.5).

To do so, peripheral blood samples were collected from 11 patients with LR-MDS (MDS with low blasts n=9, MDS with SF3B1 n=2). RNA sequencing performed in isolated monocytes. Differential expression analysis was performed utilizing the edgeR Bioconductor R package. Statistically significant differentially expressed genes (DEGs) were identified based on a FDR threshold of <0.1 and a logFC threshold of >0.58. Gene set enrichment analysis (GSEA) was performed, using well-annotated Hallmark gene sets from the Molecular Signatures Database (MSigDB) as input.

Principal Component Analysis (PCA) demonstrated a clear segregation of samples into two distinct subgroups (Subgroup_1 and _2). Differential expression analysis identified 483 DEGs upregulated in Subgroup_1 and 1035 DEGs upregulated in Subgroup_2. Pathway enrichment analysis revealed an enrichment of genes associated with oxidative phosphorylation (OXPHOS) and TNF-α signaling in Subgroup_1. Of note, Subgroup_1 exhibited an upregulation of the cholesterol homeostasis pathway, which was in line with the significant increase in total and non-HDL cholesterol and triglycerides in this group. Moreover, unsupervised clustering based on the expression levels of genes involved in inflammasome-related signatures (Basiorka et al., 2016), led to clear separation of the two groups, with Subgroup_1 displaying significantly higher expression levels of the inflammasome-related genes NRLP3 and PYCARD.

Herein, we show that lower lipid levels in LR-MDS patients is associated with a suppressed inflammatory signature in peripheral monocytes and a down-regulation in the expression of genes related to inflammasome. Considering the link between CVD and CHIP, our findings show that early administration of lipid-lowering regimens can be beneficial in patients with LR-MDS, suppressing the inflammatory potential of monocytes, a critical cell population in CVD.

Acknowledgements: Supported by the UAE-NIH Collaborative Research grant AJF-NIH-25-KU

No relevant conflicts of interest to declare.