SOHLH2 downregulation marks CD163-positive M2-like immunoregulatory marrow remodeling in acute myeloid leukemia: a single-center retrospective cohort study

Abstract

The immunosuppressive marrow niche is a driver of acute myeloid leukemia (AML) persistence, yet transcriptional signals linked to macrophage skewing remain poorly defined. SOHLH2, a tumor-suppressive transcription factor in solid cancers, has not been characterized in AML. We investigated whether reduced SOHLH2 marks expansion of a CD163-positive M2-like monocyte/macrophage compartment. Diagnostic marrow from 174 AML patients and 58 non-leukemic controls was analyzed retrospectively. SOHLH2 mRNA was quantified by GAPDH-normalized qRT-PCR, and CD163-positive enrichment was assessed by multiparameter flow cytometry with multi-marker validation. Associations were tested using correlation, staged regression, sensitivity analyses and internally validated ROC analysis. AML marrow showed lower SOHLH2 expression than control marrow (0.96 vs. 1.26 a.u.; P < 0.001) and a larger CD163-positive fraction (20.2% vs. 8.7%; P < 0.001). SOHLH2 was strongly inversely correlated with CD163 positivity (Spearman ρ=-0.69; Pearson r =-0.71; both P < 0.001), persisting after adjustment for blast percentage, FAB subtype and karyotype (partial ρ=-0.60) and across key subgroups. Validation confirmed enrichment of CD163/CD206-positive and CD163/HLA-DRlow M2-like cells with low blast contamination. Lower SOHLH2 independently marked high CD163 positivity (adjusted OR 1.94 per 0.1-unit decrease; 95% CI 1.53–2.48) and tracked cytogenetic abnormality (AUC 0.94). Exploratory analyses linked low SOHLH2 to poorer outcomes. Reduced SOHLH2 identifies a CD163-positive, M2-like, cytogenetically aberrant AML marrow state. These findings suggest SOHLH2 as a candidate marker of immunoregulatory niche remodeling and warrant prospective molecular and functional validation.