Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy that imposes great challenges in terms of drug resistance and relapse. Previous studies revealed heterogeneous leukemia cells and their relevant gene markers, such as CRIP1 as clinically prognostic in t (8;21) AML patients. However, the expression and role of CRIP1 in AML are poorly understood. We used the single-cell RNA sequencing and gene expression data from t (8;21) AML patients to analyze the immune and regulation networks of CRIP1 . Two independent cohorts from GSE37642 and The Cancer Genome Atlas (TCGA) datasets were employed as validation cohorts. In addition, the methylation data from TCGA were used to analyze the methylation effect of the CRIP1 expression. Gene expression profile from t (8;21) AML patients showed that the CRIP1 -high group exhibited an enrichment of immune-related pathways, including tumor necrosis factor (TNF)α signaling via nuclear factor kappa B (NFκB) pathways. Further studies using CIBERSORT showed that the CRIP1 -high group had a significantly higher infiltration of exhausted CD8 T cells and activated mast cells. The CRIP1 expression was validated in the GSE37642-GPL96, GSE37642-GPL570, and TCGA datasets. In addition, with the methylation data, four CpG probes of CRIP1 (cg07065217, cg04411625, cg25682097, and 11763800) were identified as negatively associated with the CRIP1 gene expression in AML patients. Our data provide a comprehensive overview of the regulation of CRIP1 expression in AML patients. The evaluation of the TNFα-NFκB signaling pathway as well as the immune heterogeneity might provide new insights for exploring improvements in AML treatment.