Associations of polymorphisms in the myeloid immunoregulatory receptor gene MRC1 with expression and prognosis in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) shows substantial biological and clinical heterogeneity that extends beyond leukemia-intrinsic genetic alterations. MRC1, which encodes the myeloid receptor CD206, has been linked to monocytic differentiation and immunoregulatory states in AML. We investigated whether the MRC1 variants rs691005 and rs2253120 are associated with AML occurrence, development and prognosis. METHODS: We genotyped rs691005 and rs2253120 in 335 patients with AML and 326 healthy controls. Their associations with AML susceptibility, cytogenetic abnormalities, risk stratification, complete remission after two treatment cycles, and overall survival (OS) were examined under co-dominant, dominant, and recessive models. Independent prognostic effects were assessed using multivariable Cox regression. The relationship between SNP and MRC1 expression was evaluated using GTEx eQTL data and genotype-stratified expression measurements in primary AML bone marrow CD34+ cells. TCGA datasets were used to assess MRC1 expression and survival in AML. Virtual MRC1 knockdown and pathway analysis was performed using a single-cell RNA-sequencing dataset generated at our center. RESULTS: Neither variant was associated with AML susceptibility, cytogenetic abnormalities, or early remission. rs691005 was associated with adverse risk stratification and showed a nominal association with shorter OS in Kaplan-Meier analysis. rs2253120 AA homozygosity was associated with improved OS after multivariable adjustment and was linked to lower MRC1 expression in GTEx and primary AML samples. Higher MRC1 expression was associated with poorer OS in TCGA-LAML. Virtual MRC1 knockdown revealed exploratory enrichment patterns related to myeloid differentiation, adhesion, cytokine production, and immune regulation. CONCLUSIONS: MRC1 rs691005 was linked to adverse risk stratification and shorter OS, whereas rs2253120 AA homozygosity was independently associated with better OS and lower MRC1 expression. These findings support a potential role for inherited variation at the MRC1 locus in the clinical and immune heterogeneity of AML.