Myelodysplastic neoplasms (MDS) are clonal disorders characterized by cytopenias, bone marrow dysplasia, and a risk of progression to acute myeloid leukemia related to myelodysplasia (AML-RM). The accumulation of driver mutations in hematopoietic stem cells (HSCs) leads to clonal expansion and ineffective hematopoiesis. Activation of innate immune pathways, particularly through Toll-like receptors (TLRs), is increasingly recognized as a key contributor to disease progression, fostering inflammation, apoptosis, and abnormal cell proliferation. Dysregulated TLR signaling and chronic inflammation disrupt bone marrow homeostasis and are frequently associated with chromosomal abnormalities and poor prognosis.

This study aimed to evaluate overall survival in relation to the expression of key genes involved in immune and inflammatory signaling.

Data from 48 patients with either MDS or AML-RM were collected and stored in the RedCap database. RNA was extracted from bone marrow and the following genes had their expression analyzed through RT-PCR: NFKB, TRAF6, MYd88, IRAK1, IRAK2 and IRAK4. 2^−ΔCT was used for this assessment, in which patients were divided into three groups based on the expression level of each gene: low expression, intermediate expression, and high expression. Furthermore, K-means clustering was applied to the 2^−ΔCT values in order to split patients into meaningful groups based on their gene expression. The elbow method was used to determine the ideal number of clusters. Kaplan-Meier estimates were used to plot survival curves, with the log-rank test being used for comparisons.

After splitting the patients by gene expression, no gene emerged as a moderator of survival (p = 0.92, 0.63, 0.54, 0.89, 0.36, and 0.64, respectively for NFKB, TRAF6, MYd88, IRAK1, IRAK2 and IRAK4). Through the elbow method, the ideal number of gene expression clusters was two, defining two clusters that only differed significantly by their expression of IRAK4 (p = 0.03, 8 patients in the IRAK4-high cluster). Although the IRAK4-high cluster had lower median survival (1.8 months vs 4 months for the IRAK4-low cluster), no significant differences emerged (p = 0.32).

Our findings suggest that the isolated expression of innate immune signaling genes does not independently predict survival in patients with MDS or AML-RM. These results underscore the multifactorial nature of MDS pathogenesis, where gene expression patterns may interact with other biological and clinical variables. Notably, the potential relevance of IRAK4 warrants further investigation in larger cohorts to clarify its prognostic value and biological significance in disease progression.